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Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US); 2012.

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Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition.

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Mossy Fiber Sprouting in the Dentate Gyrus


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Aberrant sprouting of granule cell axons (mossy fibers) into the inner molecular layer of the dentate gyrus was first described nearly 40 years ago in lesion studies designed to evaluate reactive synaptogenesis. Later, mossy fiber sprouting was discovered in patients with temporal lobe epilepsy. The cause/effect relationship between mossy fiber sprouting and epileptogenesis is unclear and controversial. Some propose it creates a positive-feedback seizure-generating circuit. Others argue that sprouted mossy fibers preferentially excite inhibitory interneurons, thereby controlling seizure activity. This chapter reviews the literature on mossy fiber sprouting with respect to the following questions: Under what circumstances does it occur? How does it develop? And, what are the functional consequences?


Granule cell axons (mossy fibers) project into the dentate hilus and stratum lucidum of CA3 in rodents1 and other species, including humans.2 Mossy fibers synapse with inhibitory interneurons, hilar mossy cells, and CA3 pyramidal cells,3 but only very rarely with other granule cells (see below). Consequently, most granule cells normally do not display functional, monosynaptic, recurrent excitation.4 A minor mossy fiber projection into the granule cell layer can be visualized with the Timm stain, which generates opaque, silver particles specifically within zinc-rich mossy fiber boutons.5 At all septotemporal levels of the hippocampus, occasional scattered dendrites and cell bodies of interneurons in the granule cell layer are outlined by Timm-positive punctae,6 which electron microscopy has identified as mossy fiber synaptic boutons.7 This pattern of Timm staining in the granule cell layer appears to increase with age.8 At the temporal pole of the hippocampus, Timm staining reveals mossy fiber projections into the inner molecular layer that target granule cell dendrites.5 This minor, recurrent, excitatory pathway also increases with age.9–12 The more extensive epilepsy-related recurrent mossy fiber pathway is an expansion of the normal, minimal circuit already present.13

Aberrantly high levels of mossy fiber sprouting were first discovered during experiments investigating lesion-induced changes in neuronal connectivity. After transection of perforant path input to the dentate gyrus in young rats, black Timm staining was detected in the inner molecular layer.14 More extensive and consistent mossy fiber sprouting developed after lesioning commissural/associational input to the inner molecular layer.6 Electron microscopy revealed that lesion-induced sprouted mossy fibers synapse with granule cell dendrites.6,15

Mossy fiber sprouting was first found in patients with temporal lobe epilepsy by Scheibel et al.16 who reported Golgi-stained mossy fibers project from the hilus, through the granule cell layer, and into the molecular layer, where their boutons appose granule cell dendrites. Later, Nadler et al.17 discovered extensive mossy fiber sprouting in rats that had been treated one month earlier with the excitotoxant kainic acid. Figure 1 shows mossy fiber sprouting in epileptic pilocarpine-treated rats. Perhaps because of the technical challenges of using the Golgi stain to follow individual granule cell axons, mossy fiber sprouting in human epileptic tissue was initially reported as rare (< 1% of granule cells).16 However, later studies used Timm staining and dynorphin-immunoreactivity as markers for mossy fibers and found substantial sprouting in patients with mesial temporal lobe epilepsy.10,18–20 Subsequently, mossy fiber sprouting was discovered in many different epilepsy-related conditions and some non-epileptic conditions (Table 1).

Figure 1. Mossy fiber sprouting in epileptic pilocarpine-treated rats.

Figure 1

Mossy fiber sprouting in epileptic pilocarpine-treated rats. A1 Timm staining of the dentate gyrus (h=hilus, g=granule cell layer, m=molecular layer) and CA3 region. A2 Magnified view of boxed region in A1 shows a dense band of black Timm-staining in (more...)

Table 1. Conditions in which mossy fiber sprouting occurs in the dentate gyrus (early references indicated).

Table 1

Conditions in which mossy fiber sprouting occurs in the dentate gyrus (early references indicated).

Temporal lobe epilepsy, the condition most frequently associated with mossy fiber sprouting, is the most common type of epilepsy in adults.21 Some patients have a lesion (a hamartoma or glioma, for example) in their temporal lobe, but most have mesial temporal lobe epilepsy, which typically involves extensive neuron loss especially in the hippocampus and in at least some cases a history of a precipitating injury.22,23 Although robust mossy fiber sprouting is a common pathological finding in patients with mesial temporal lobe epilepsy,24,25 there are exceptions.26,27 Lynd-Balta et al.28 proposed young children with mesial temporal lobe epilepsy develop mossy fiber sprouting long after other changes, including neuron loss and altered expression of glutamate receptors. However, other investigators found mossy fiber sprouting similar to that of adult patients in children as young as 5.5 months old.29 Mossy fiber sprouting does not occur exclusively in patients with mesial temporal lobe epilepsy. It also occurs in children secondary to cortical dysplasias without obvious hippocampal damage.30 In those cases, however, the amount of sprouting is less than in children with hippocampal seizures.29,31 On average, adult patients with mesial temporal lobe epilepsy have more mossy fiber sprouting than those with lesion-related temporal lobe epilepsy, but there is overlap between groups.25 Mossy fiber sprouting can occur in epileptic patients without mesial temporal lobe epilepsy.32 And, mild mossy fiber sprouting has been reported in patients with bipolar disorder but not epilepsy.33 To better understand the circumstances that result in mossy fiber sprouting, it helps to consider the molecular and cellular mechanisms underlying its development.


Mechanisms underlying mossy fiber sprouting remain unclear, but available evidence suggests likely triggers. One is seizure activity, which appears capable of causing mild mossy fiber sprouting without obvious neuron loss.34–39 However, seizure activity alone is not always sufficient, because many seizures can propagate through the dentate gyrus without causing mossy fiber sprouting, as in Mongolian gerbils with inherited epilepsy.7,40 Intense mossy fiber sprouting, like that found in patients with mesial temporal lobe epilepsy, appears to require deafferentation of granule cells either by transecting axons6 or killing presynaptic neurons.17,41,42 Hilar mossy cells give rise to the associational pathway of the dentate gyrus (and in rodents, the commissural pathway),43,44 account for ~60% of all hilar neurons,45–47 and synapse with granule cell dendrites in the inner molecular layer,48 which also are the primary target of sprouted mossy fibers. Extent of mossy fiber sprouting correlates with hilar neuron loss in patients with mesial temporal lobe epilepsy19,20,26 and in laboratory animal models.49–52 More specifically, mossy cell loss correlates with mossy fiber sprouting in epileptic pilocarpine-treated rats.47 However, fundamental questions persist. Is mossy cell loss alone sufficient to cause mossy fiber sprouting?53 What is it about mossy cell loss that facilitates mossy fiber sprouting: granule cell deafferentation, removal of a synaptic target of mossy fibers, or both?54 Complicating the issue, the most common experimental method used to produce mossy fiber sprouting is status epilepticus, which involves many other potential triggers in addition to mossy cell loss.

Whatever the events are that trigger mossy fiber sprouting, presumably they are transduced to granule cells as molecular cues that activate signaling pathways to coordinate mossy fiber growth and synaptogenesis. c-Fos was proposed as an early step in the process.35 However, increased expression of c-fos and some other immediate early genes do not appear necessary for mossy fiber sprouting.55,56 Increased expression of GAP-43, a membrane-bound protein concentrated at growth cones and developing presynaptic terminals, was proposed to promote mossy fiber sprouting.24,57–60 In addition to GAP-43, tubulins61 and microtubule-associated proteins62 could be involved in mossy fiber sprouting. However, in regard to the molecular mechanisms underlying mossy fiber sprouting, BDNF has received the most attention. BDNF expression increases in the dentate gyrus after seizures.63,64 BDNF promotes granule cell hypertrophy65 and mossy fiber branching.66 When infused in control animals, BDNF causes seizure activity and mild mossy fiber sprouting.67 And, electroconvulsive seizure-induced sprouting is diminished in BDNF heterozygote knockout mice.38 In contrast, other reports challenge the role of BDNF in mossy fiber sprouting. Mild mossy fiber sprouting develops in slice cultures from homozygote BDNF knockout mice68 and after kindling in heterozygote BDNF knockout mice.69 Transgenic overexpression of BDNF does not cause mossy fiber sprouting.70 The timing of BDNF expression relative to development of mossy fiber sprouting has been questioned.71 And, Vaidya et al.38 reported that BDNF infusion does not cause mossy fiber sprouting. Nevertheless, strong evidence comes from organotypic culture experiments that induced mossy fiber sprouting by application of BDNF or a GABAA receptor antagonist.72 In those experiments, an L-type calcium channel blocker, sodium channel blocker, TrkB inhibitor, function-blocking anti-BDNF antibody, and transfection with dominant-negative TrkB each reduced mossy fiber sprouting. Thus, it seems likely that BDNF plays a role in mossy fiber sprouting but specific signaling pathways and molecular targets remain unclear.

The laminar specificity of sprouted mossy fibers is remarkable. For example, in most hippocampal slice cultures the outer molecular layer is almost completely denervated but is relatively unstained for mossy fibers, which remain confined to the inner molecular layer.42 Such specificity suggests strong attractant and/or repulsive extracellular signals. Although several molecular candidates have been proposed – including NCAMs,73,74 tenascin-C,75 Sema3A,76 and hyaluronan77 – none can fully account for precise targeting by sprouted mossy fibers, which remains an important area for research. In summary, there still is much to learn about the molecular mechanisms involved in transducing triggering stimuli, coordinating mossy fiber growth, and directing mossy fibers to their synaptic targets.

At the cellular level, an increasingly detailed picture of mossy fiber sprouting has emerged. After status epilepticus in rats, ~3 months are required for mossy fiber sprouting to fully develop.12,78,79 Once fully developed, the proportion of granule cells with sprouted mossy fibers appears to be ~60% in patients with mesial temporal lobe epilepsy80 and laboratory animal models,81–84 but more precise estimates are needed. Recent findings suggest only new adult-generated granule cells sprout mossy fibers into the molecular layer. Granule cell neurogenesis normally continues throughout life. For example, in young adult control rats the number of new granule cells generated each month is 6% of the total population.85 Granule cell neurogenesis accelerates after status epilepticus86 or even milder seizure activity.87 Although earlier studies questioned the role of newborn granule cells in mossy fiber sprouting,88,89 later work showed that granule cells born up to 4 weeks before status epilepticus90 and up to 4 days after can develop aberrant mossy fiber projections to the inner molecular layer, whereas older granule cells (born ≥ 7 weeks before status epilepticus) do not.91 Identification of newborn granule cells as the source of aberrant mossy fibers is an important advance in our understanding of how mossy fiber sprouting develops, but questions persist. Why do newborn granule cells develop aberrant connections? Are the underlying causes attributable to intrinsic, perhaps epigenetic, changes in granule cells, to extrinsic cues in the microenvironment, or to both? Are underlying causes transient or permanent - and if permanent, can they be reversed? Do all newborn granule cells form aberrant connections or just a subset? And, how long following a precipitating injury will newborn granule cells continue to develop aberrant connections?

Human epileptic tissue displays evidence of ongoing synaptic reorganization years after precipitating injuries and the onset of spontaneous seizures.24,74,80 Although these results might suggest mossy fiber sprouting continually progresses and becomes increasingly more severe with time, in laboratory animal models, which can be evaluated more extensively and with more temporal resolution, levels of mossy fiber sprouting appear to plateau after 3 months.12 Together, these findings and the neurogenesis data described above suggest older, sprouted mossy fibers might be replaced by new ones. If aberrant circuits continually turnover, there may be opportunities to interrupt the pathophysiological process even after robust mossy fiber sprouting develops. Consistent with this notion, after a 45 day delay, during which time some sprouting is likely to have developed, grafts of CA3 pyramidal neurons reduce mossy fiber sprouting following kainate-infusion.79 Furthermore, levels of mild mossy fiber sprouting after experimental electroconvulsive treatment peak and then decrease at later time points, suggesting at least partial reversal.38 Therefore, despite evidence that mossy fiber sprouting is long-lasting or even permanent,32,78,92 it might be worthwhile to further test its stability.

At the microcircuit level, in vivo spatial features of mossy fiber sprouting have been evaluated using axon tracers81 and intracellular labeling.82 Individual granule cells extend mossy fibers into the inner molecular layer over an area with an average radius of 600 μm, which is comparable to the span of hilar collateral projections in control animals. Plotting the corresponding area onto a calibrated, flattened map of the rat dentate gyrus,93 and using an estimate of 1 million granule cells per rat dentate gyrus,94 one can predict that ~42,000 granule cells are within reach of one granule cell’s sprouted mossy fibers. Integrating axon-length-per-cell with synapse-density-per-axon-length suggests each granule cell that sprouts mossy fibers into the molecular layer forms an average of ~500 new synapses with other granule cells.95 If one assumes that each new synapse is with a different granule cell and ~60% of granule cells in epileptic rats sprout mossy fibers, then the probability of finding a monosynaptically coupled granule cell within another cell’s reach is 0.7% - which is consistent with experimental results.96 In addition to mossy fiber projections into the inner molecular layer, granule cells in epileptic animals have greater axon length in the hilus,82 increased branching of hilar collaterals,83 and more boutons in the hilus.81 In the hilus of epileptic animals, therefore, mossy fibers might hyperinnervate surviving neurons, consistent with recent findings from recordings of hilar somatostatin interneurons.97 Epilepsy-related mossy fiber sprouting also occurs in stratum oriens of CA3,98 but the present review focuses on the dentate gyrus.

In addition to their normal synaptic targets, in epileptic tissue sprouted mossy fibers form asymmetric (excitatory) synapses with ectopic granule cells in the hilus,99,100 with granule cell basal dendrites in the hilus,101,102 with granule cell somata in the granule cell layer,83,103 and with granule cell apical dendrites in the granule cell layer and inner molecular layer12,20,101,104–106 (including occasional autapses83,101). In the inner molecular layer, ~90% of mossy fiber synapses are with dendritic spines, the remainder with dendritic shafts. Mossy fiber synapses with granule cells are abundant, accounting for ~50% of all inner molecular synapses in epileptic pilocarpine-treated rats.94,100 Compared to other excitatory synapses in the inner molecular layer, mossy fiber synapses appear to be larger and are more likely to be perforated,94,105 features that suggest greater synaptic strength.107,108 Overall, there is considerable anatomical evidence that mossy fiber sprouting creates a positive-feedback circuit among granule cells.

Sprouted mossy fibers also synapse with inhibitory interneurons but much less frequently than with granule cells.83,105 Some have proposed that sprouted mossy fibers hyperinnervate parvalbumin-immunoreactive basket cells.109,110 Others have countered that even in control tissue those interneurons receive high levels of mossy fiber input.111 If interneurons were hyperinnervated by excitatory synapses after mossy fiber sprouting, one would predict the frequency of spontaneous inhibitory postsynaptic currents in granule cells to be more sensitive to glutamatergic receptor antagonists, which was reported.112 However, one also would expect that miniature excitatory postsynaptic current frequency in basket cells – a more direct measure of the number of glutamatergic synapses impinging upon basket cells – would increase as mossy fiber sprouting develops; however, it does not.113 In vivo biocytin-labeling and 3-dimensional reconstruction of serial electron micrographs of sprouted mossy fibers revealed only ~5% of synapses formed by sprouted mossy fibers in the granule cell layer and molecular layer are with GABA-immunoreactive neurons, the other ~95% are with granule cells.95 Integrating synaptic density, synaptic target frequency, and sprouted mossy fiber length, these findings suggest the average granule cell with sprouted mossy fiber collaterals forms 20 times more new synapses with granule cells than with interneurons.


As expected from anatomical evidence reviewed above, mossy fiber sprouting creates an aberrant, recurrent, excitatory circuit. Functional positive-feedback among granule cells has been demonstrated with varying experimental approaches and degrees of confidence. In animals with mossy fiber sprouting, but not in controls, in vivo perforant path stimulation evokes a delayed current sink in the inner molecular layer114 and reverberating field potential responses, which are consistent with positive-feedback among granule cells.50,82,115 As in hippocampal slice studies,116 reverberating responses in vivo become most apparent after inhibition is blocked. A limitation of the in vivo approach, however, is that perforant path stimulation activates many circuits in addition to sprouted mossy fibers. In hippocampal slices, especially with GABAA receptors at least partially blocked or extracellular potassium ion concentration elevated, antidromic stimulation of mossy fibers evokes depolarizing synaptic responses in granule cells more frequently after sprouting, consistent with the formation of recurrent, excitatory connections.13,26,116–119 However, even with more focal electrical stimulation in hippocampal slice experiments compared to in vivo studies, axons other than sprouted mossy fibers could be activated, including projections from mossy cells and CA3 pyramidal cells. More specific activation of granule cells with glutamate uncaging or glutamate microdrop application evokes synaptic responses in other granule cells more frequently in slices with mossy fiber sprouting compared to controls.120–123 Although unlikely, the possibility of polysynaptic activation through surviving mossy cells and CA3 pyramidal cells cannot be excluded completely, even with these methods. Scharfman et al.96 provided the strongest evidence to date that mossy fiber sprouting creates a functional positive-feedback circuit among granule cells. In hippocampal slices from epileptic pilocarpine-treated rats with sprouting, but not in controls, granule cells generate monosynaptic excitatory potentials in other granule cells. The probability of monosynaptic coupling between granule cells after sprouting is 0.66%,96 which is similar to estimates based on anatomical data (see above) and a level approaching that normally found among CA3 pyramidal cells.124 The average amplitude of granule cell-to-granule cell synaptic responses is ~2 mV, and their failure rate is 60–70%,96,122,125 which is not unusual for excitatory synapses in cortical areas. Granule cell-to-granule cell synapses utilize AMPA/KA- and to a smaller extent NMDA-receptors.13,122 Kainate-receptors account for an unusually large amount of charge transfer at mossy fiber synapses with granule cells.126 Granule cell-to-granule cell synapses can be presynaptically blocked by type II metabotropic glutamate receptors, presynaptically facilitated by kainate-receptors, and they display frequency-dependent short-term plasticity intermediate of that of normal mossy fiber synapses with interneurons and CA3 pyramidal cells.125

Thus, both anatomical and functional evidence confirms that after mossy fiber sprouting, granule cells receive abnormally high levels of synaptic input from other granule cells, which is minimal in control animals. The frequency of spontaneous excitatory postsynaptic currents (EPSCs) in granule cells increases with mossy fiber sprouting,121,127 which could be attributable to more excitatory synapses. However, another possibility is increased levels of activity in slices from epileptic animals. Consistent with the latter possibility, the frequency of miniature EPSCs - which depends on numbers of synapses and probability of release but not action potentials - is similar in granule cells before and after mossy fiber sprouting,126 not increased as would be expected if granule cells were to receive more synapses after sprouting. A stereological, electron microscopy study estimated numbers of excitatory synapses with proximal dendrites per granule cell in control rats, in rats 5 days after status epilepticus, and in chronically epileptic animals.94 Shortly after status epilepticus, which kills many hilar mossy cells, the number of synapses is reduced to < 40% of control levels, but weeks later recovers to ~85% of controls. Sprouted mossy fibers are likely to account for much, if not all, of the recovery. Together, these findings suggest mossy fiber sprouting nearly replaces but does not exceed the original number of inner molecular layer glutamatergic synapses lost by granule cells during precipitating injuries.

The cellular electrophysiological evidence reviewed above demonstrates effects of mossy fiber sprouting at the synaptic level. However, the most important question about mossy fiber sprouting from a clinical standpoint is whether it is epileptogenic, compensatory, or neither. The extensive literature on this topic will be reviewed beginning with relevant hypotheses. Shortly after it was discovered in kainate-treated rats, Tauck and Nadler117 proposed mossy fiber sprouting creates an aberrant positive-feedback network among granule cells that synchronizes their activity and facilitates seizure activity. After many years of accumulating data, Nadler restated the hypothesis and added that “the recurrent mossy fiber pathway promotes seizure propagation from the entorhinal cortex to the hippocampus mainly when granule cells are driven at a frequency appropriate to promote synaptic facilitation” [≥1 Hz].125 Buhl et al.112 suggested that sprouted mossy fibers contribute to seizures during periods of high activity but through a different mechanism. They proposed that changes in subunit expression of GABAA receptors on granule cells in epileptic animals makes them vulnerable to negative modulation by zinc. Further, they proposed that during periods of intense activity, granule cells synaptically release zinc from sprouted mossy fibers, which diffuses to GABAergic synapses and reduces inhibition when it is critically needed. Thus, two hypotheses (recurrent excitation and zinc-induced collapse of inhibition) contend that mossy fiber sprouting is epileptogenic. In contrast, Sloviter128 proposed sprouted mossy fibers preferentially synapse with basket cells and restore powerful recurrent inhibition lost after injuries kill hilar mossy cells. Recently, Sloviter et al.110 restated the view that “mossy fiber sprouting may play a clinically important role in retarding seizure spread (keeping subclinical seizures subclinical).” Simmons et al.127 proposed that effects of mossy fiber sprouting are mixed. Some of their data support the recurrent excitation hypothesis, but they also proposed sprouted mossy fibers release opioid peptides that have anticonvulsant effects. Other inhibitory transmitters that could be released by sprouted mossy fibers include NPY129 and GABA.130 Finally, Gloor131 reviewed the literature on neuron loss in temporal lobe epilepsy, considered evidence of synaptic reorganization, and suggested that mossy fiber sprouting might be an epiphenomenon with neither pro- or anti-epileptic effects. Investigators have worked within the context of these diverging hypotheses. For purposes of review, reports on functional consequences of mossy fiber sprouting are summarized below in three categories: kindling studies, experiments that evaluated evoked seizure-like events, and investigations that measured frequencies of spontaneous seizures in patients with temporal lobe epilepsy and laboratory animal models.

In early kindling studies, hyperexcitability and mossy fiber sprouting were shown to develop in parallel, suggesting sprouting might be epileptogenic.34,92 Later studies revealed that hyperexcitability and mossy fiber sprouting can be dissociated.132,133 But in a broader sense, implications of kindling studies for the role of mossy fiber sprouting in temporal lobe epileptogenesis might be limited. Animals do not display spontaneous seizures unless kindled very extensively - for example, ~100 times in rats.134 More typical kindling paradigms that involve only 10–20 stimulations generate levels of mossy fiber sprouting far below that found in many patients with mesial temporal lobe epilepsy and other laboratory animal models.41 Instead, kindling might more closely model the mild mossy fiber sprouting found with experimental conditions that kill few, if any, neurons and the mild mossy fiber sprouting found in some patients in which hippocampal neurons are largely spared. This mild form of mossy fiber sprouting might be an effect, not a cause, of seizure activity.

Another set of studies tested whether evoked seizure-like responses correlate with extent of mossy fiber sprouting. Simulations run on a computer model of dentate circuitry suggested mossy fiber sprouting has little effect on granule cell activity and attributed the lack of effect to the granule cells’ stabilizing intrinsic physiological properties.135 However, later, more realistic computer models found mossy fiber sprouting promotes spread of seizure-like activity.136 A strength of the in silico approach is the ability to specifically test individual parameters while leaving other conditions unchanged; these studies showed that mossy fiber sprouting alone is sufficient to cause hyperexcitability in the modeled dentate gyrus.137 Furthermore, incorporating a small number of highly interconnected granule cells greatly increases network activity.138 Whether granule cell network hubs actually exist in epileptic tissue and generate seizures is an intriguing prediction to be tested in future experiments. In addition to computer models, actual epileptic tissue has been evaluated. In organotypic slice cultures, kainate treatment causes mossy fiber sprouting but does not affect seizure activity.139 In contrast, in experiments with acute slices, evoked seizure-like responses by granule cells are more likely after mossy fiber sprouting develops in patients with mesial temporal lobe epilepsy140 and in rodent models.120,121,141,142 In summary, much, but not all, computer modeling and experimental slice data are consistent with the hypothesis that mossy fiber sprouting is epileptogenic. Compared to in vivo experiments, these studies reduced confounding influences from outside structures and more specifically evaluated the dentate gyrus region where sprouting occurs. However, caveats include the unclear relevance of computer models and hippocampal slice preparations to in vivo situations, the common requirement for pro-convulsant conditions (for example GABAA receptor antagonists and elevated potassium ion concentrations) to unmask seizure-like responses, and dependency on provoking stimuli, which is unlike typically unprovoked seizures in patients.

Spontaneous seizures can be measured in vivo and compared with extent of mossy fiber sprouting in laboratory animal models and when tissue is surgically resected to treat patients. Some studies found correlations between the extent of mossy fiber sprouting and seizure frequency,41,83,143–146 but many have not.26,28,50–52,54,78,128,147–158 Thus, although a loose association between the development of epilepsy and moderate-to-intense levels of mossy fiber sprouting is commonly reported (in other words, epileptic animals are more likely to display mossy fiber sprouting than non-epileptic individuals), consistently replicable, statistically significant correlations between seizure frequency and mossy fiber sprouting are lacking. Most in vivo evidence listed above, therefore, supports the hypothesis that mossy fiber sprouting might be an epiphenomenon without major pro- or anti-epileptic effects. However, seizure monitoring methods used by many previous experiments suffered from limited sampling and might have been statistically under-powered, which increases variability in seizure frequency data, making it more difficult to detect subtle correlations. Another potential source of variability are myriad other parameters that might change independently of mossy fiber sprouting and have confounding effects on seizure frequency. Ideally, to more rigorously test its role in epileptogenesis, one would like to specifically block only the development of mossy fiber sprouting after an epileptogenic injury, carefully monitor the frequency and severity of spontaneous seizures, and compare the results to a similarly treated group in which mossy fiber sprouting developed.

Most efforts to block mossy fiber sprouting have been unsuccessful, despite testing reasonable candidate mechanisms. One prior attempt neutralized nerve growth factor with antibodies, which suppressed sprouting by cholinergic axons but not mossy fibers.159 Treatment with the anticonvulsant vigabatrin did not block mossy fiber sprouting when administered to rats after kainate-induced status epilepticus.160 Blocking neural activity by continuously infusing tetrodotoxin into the dentate gyrus for a month after status epilepticus did not suppress mossy fiber sprouting and might have made it worse.161 It was reported that blocking protein synthesis with cycloheximide around the time of epileptogenic injury reduced mossy fiber sprouting.53,162,163 However, cycloheximide pretreatment reduces excitotoxic damage during status epilepticus;87,89,164 therefore, mossy fiber sprouting may have been reduced indirectly by reducing hilar neuron loss.165 Furthermore, when administered systemically as in the original experiments166 or infused directly into the dentate gyrus167 cycloheximide’s effect on mossy fiber sprouting could not be reproduced by other investigators. Therefore, it is doubtful that transiently blocking protein synthesis directly prevents mossy fiber sprouting.

Mossy fiber sprouting presumably begins with formation of growth cones, and previous attempts targeted growth cone function by blocking L-type calcium channels and inhibiting the calcium-activated phosphatase, calcineurin. Systemic administration of the L-type calcium channel blocker nicardipine was reported to suppress mossy fiber sprouting after pilocarpine-induced status epilepticus.168 And, the calcineurin inhibitor FK506 was reported to inhibit kindling169 and block mossy fiber sprouting.170 However, after a month of continuous, direct infusion into the dentate gyrus of nicardipine, FK506, or cyclosporin A (another calcineurin inhibitor), extent of mossy fiber sprouting was similar in infused versus noninfused hippocampi of rats that had experienced status epilepticus.171

The ketogenic diet was reported to reduce mossy fiber sprouting after kainate-induced status epilepticus,172 but sample sizes in that study were small and results should be verified. Chronic treatment with oral lithium at therapeutically relevant concentrations was reported to suppress mossy fiber sprouting after pilocarpine-induced status epilepticus.173 However, in that study, status epilepticus was curtailed early, and the level of excitotoxicity appeared insufficient to produce an adequate baseline level of mossy fiber sprouting for comparison. The NR2B-selective NMDA antagonist (Ro 25,6981) suppressed mossy fiber sprouting in organotypic cultures,174 but it is unclear whether it would be effective in vivo. Grafting embryonic CA3 pyramidal cells into the hippocampus reduces mossy fiber sprouting after kainate-induced status epilepticus,79 but grafted neurons sprout axons into the inner molecular layer of the dentate gyrus, suggesting they might suppress development of one recurrent excitatory circuit (among granule cells) by establishing another aberrant positive-feedback circuit in its place (a disynaptic circuit between CA3 pyramidal cells and granule cells).

Recently, a new treatment was discovered that suppresses mossy fiber sprouting. Rapamycin administered systemically175 or directly infused into the dentate gyrus176 reduces mossy fiber sprouting after chemoconvulsant-induced status epilepticus in rats. Rapamycin inhibits the mTOR signaling pathway that transduces extracellular signals, including BDNF, to control protein synthesis and cell growth.177,178 Systemic treatment with rapamycin was reported to suppress both mossy fiber sprouting and seizure frequency in rats.175 In pilocarpine-treated mice, however, systemic rapamycin suppressed mossy fiber sprouting but did not affect seizure frequency.179 Possible explanations for the apparently contradictory results include a confounding anticonvulsant effect of rapamycin specifically in rats.180 In conclusion, the role of mossy fiber sprouting in epileptogenesis remains unclear. As additional methods are discovered to block its development selectively, more opportunities will arise to test its functional effects. In addition to granule cells, epilepsy-related axon reorganization occurs among other excitatory neurons, including CA3 pyramidal cells,181,182 CA1 pyramidal cells,183 subicular neurons,152 and neocortical neurons.184 Therefore, future lessons learned from continued study of mossy fiber sprouting might have more general relevance for a broad range of patients with epilepsy and other brain disorders that involve synaptic reorganization.


The author’s work is supported by NIH-NINDS.


Ramón y Cajal S. Histology of the nervous system of man and vertebrates. Swanson N, Swanson LW, translators. New York: Oxford University Press; 1995. pp. 614–625.
Lim C, Blume HW, Madsen JR, Saper CB. Connections of the hippocampal formation in humans: I. The mossy fiber pathway. J Comp Neurol. 1997;385:325–351. [PubMed: 9300763]
Acsády L, Kamondi A, Sik A, Freund T, Buzsáki G. GABAergic cells are the major postsynaptic targets of mossy fibers in the rat hippocampus. J Neurosci. 1998;18:3386–3403. [PubMed: 9547246]
Fricke RA, Prince DA. Electrophysiology of dentate gyrus granule cells. J Neurophysiol. 1984;51:195–209. [PubMed: 6707720]
Haug F-M Š. Light microscopical mapping of the hippocampal region, the piriform cortex and the corticomedial amygdaloid nuclei of the rat with Timm’s sulphide silver method. Z Anat Entwickl-Gesch. 1974;145:1–27. [PubMed: 4450596]
Laurberg S, Zimmer J. Lesion-induced sprouting of hippocampal mossy fiber collaterals to the fascia dentata in developing and adult rats. J Comp Neurol. 1981;200:433–459. [PubMed: 7276246]
Ribak CE, Peterson GM. Intragranular mossy fibers in rats and gerbils form synapses with the somata and proximal dendrites of basket cells in the dentate gyrus. Hippocampus. 1991;1:355–364. [PubMed: 1669315]
Wolfer DP, Lipp HP. Evidence for physiological growth of hippocampal mossy fiber collaterals in the guinea pig during puberty and adulthood. Hippocampus. 1995;5:329–340. [PubMed: 8589796]
Cassell MD, Brown MW. The distribution of Timm’s stain in the nonsulphide-perfused human hippocampal formation. J Comp Neurol. 1984;222:461–471. [PubMed: 6199383]
Sutula T, Cascino G, Cavazos J, Parada I, Ramirez L. Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Ann Neurol. 1989;26:321–330. [PubMed: 2508534]
Qiao X, Noebels JL. Developmental analysis of hippocampal mossy fiber outgrowth in a mutant mouse with inherited spike-wave seizures. J Neurosci. 1993;12:4622–4635. [PubMed: 8229188]
Okazaki MM, Evenson DA, Nadler JV. Hippocampal mossy fiber sprouting and synapse formation after status epilepticus in rats: visualization after retrograde transport of biocytin. J Comp Neurol. 1995;352:515–534. [PubMed: 7721998]
Okazaki MM, Molnár P, Nadler JV. Recurrent mossy fiber pathway in rat dentate gyrus: synaptic currents evoked in presence and absence of seizure-induced growth. J Neurophysiol. 1999;81:1645–1660. [PubMed: 10200201]
Zimmer J. Changes in the Timm sulfide silver staining pattern of the rat hippocampus and fascia dentata following early postnatal deafferentation. Brain Res. 1973;64:313–326. [PubMed: 4131249]
Frotscher M, Zimmer J. Lesion-induced mossy fibers to the molecular layer of the rat fascia dentata: identification of postsynaptic granule cells by the Golgi-EM technique. J Comp Neurol. 1983;215:299–311. [PubMed: 6189867]
Scheibel ME, Crandall PH, Scheibel AB. The hippocampal-dentate complex in temporal lobe epilepsy. Epilepsia. 1974;15:55–80. [PubMed: 4523024]
Nadler JV, Perry BW, Cotman CW. Selective reinnervation of hippocampal area CA1 and the fascia dentata after destruction of CA3-CA4 afferents with kainic acid. Brain Res. 1980;182:1–9. [PubMed: 7350980]
de Lanerolle NC, Kim JH, Robbins RJ, Spencer DD. Hippocampal interneuron loss and plasticity in human temporal lobe epilepsy. Brain Res. 1989;495:387–395. [PubMed: 2569920]
Houser CR, Miyashiro JE, Swartz BE, Walsh GO, Rich JR, Delgado-Escueta AV. Altered patterns of dynorphin immunoreactivity suggest mossy fiber reorganization in human hippocampal epilepsy. J Neurosci. 1990;10:267–282. [PubMed: 1688934]
Babb TL, Kupfer WR, Pretorius JK, Crandall PH, Levesque MF. Synaptic reorganization by mossy fibers in human epileptic fascia dentata. Neuroscience. 1991;42:351–363. [PubMed: 1716744]
Engel J Jr, Williamson PD, Wieser HG. Mesial temporal lobe epilepsy. In: Engel J Jr, Pedley TA, editors. Epilepsy: a comprehensive textbook. Philadelphia: Lippincott-Raven; 1997. pp. 2417–2426.
Babb TL, Brown WJ. Pathological findings in epilepsy. In: Engel J Jr, editor. Surgical treatment of the epilepsies. New York: Raven; 1987. pp. 511–540.
Mathern GW, Babb TL, Vickrey BG, Melendez M, Pretorius JK. The clinical-pathogenic mechanisms of hippocampal neuron loss and surgical outcomes in temporal lobe epilepsy. Brain. 1995;118:105–118. [PubMed: 7894997]
Proper EA, Oestreicher AB, Jansen GH, Veelen CWMv, van Rijen PC, Gispen WH, de Graan PNE. Immunohistochemical characterization of mossy fibre sprouting in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Brain. 2000;123:19–30. [PubMed: 10611117]
Mathern GW, Pretorius JK, Babb TL. Quantified patterns of mossy fiber sprouting and neuron densities in hippocampal and lesional seizures. J Neurosurg. 1995;82:211–219. [PubMed: 7815148]
Masukawa LM, Uruno K, Sperling M, O’Connor MJ, Burdette LJ. The functional relationship between antidromically evoked field responses of the dentate gyrus and mossy fiber reorganization in temporal lobe epileptic patients. Brain Res. 1992;579:119–127. [PubMed: 1623399]
de Lanerolle NC, Kim JH, Williamson A, Spencer SS, Zaveri HP, Eid T, Spencer DD. A retrospective analysis of hippocampal pathology in human temporal lobe epilepsy: evidence for distinctive patient subcategories. Epilepsia. 2003;44:677–687. [PubMed: 12752467]
Lynd-Balta E, Pilcher WH, Joseph SA. AMPA receptor alterations precede mossy fiber sprouting in young children with temporal lobe epilepsy. Neuroscience. 2004;126:105–114. [PubMed: 15145077]
Mathern GW, Babb TL, Mischel PS, Vinters HV, Pretorius JK, Leite JP, Peacock WJ. Childhood generalized and mesial temporal epilepsies demonstrate different amounts and patterns of hippocampal neuron loss and mossy fibre synaptic reorganization. Brain. 1996;119:965–987. [PubMed: 8673505]
Mathern GW, Leite JP, Pretorius JK, Quinn B, Peacock WJ, Babb TL. Children with severe epilepsy: evidence of hippocampal neuron losses and aberrant mossy fiber sprouting during postnatal granule cell migration and differentiation. Dev Brain Res. 1994;78:70–80. [PubMed: 8004775]
Ying Z, Babb TL, Hilbig A, Wylie E, Mohamed A, Bingaman W, Prayson R, Staugaitis S, Najm I, Lüders HO. Hippocampal chemical anatomy in pediatric and adolescent patients with hippocampal or extrahippocampal epilepsy. Dev Neurosci. 1999;21:236–247. [PubMed: 10575247]
Thom M, Martinian L, Catarino C, Yogarajah M, Koepp MJ, Caboclo L, Sisodiya SM. Bilateral reorganization of the dentate gyrus in hippocampal sclerosis: a postmortem study. Neurology. 2009;73:1033–1040. [PMC free article: PMC2754323] [PubMed: 19710404]
Dowlatshahi D, MacQueen G, Wang J-F, Chen B, Young LF. Increased hippocampal supragranular Timm staining in subjects with bipolar disorder. NeuroReport. 2000;11:3775–3778. [PubMed: 11117489]
Sutula T, Xiao-Xian H, Cavazos J, Scott G. Synaptic reorganization in the hippocampus induced by abnormal functional activity. Science. 1988;239:1147–1150. [PubMed: 2449733]
Watanabe Y, Johnson RS, Butler LS, Binder DK, Spiegelman BM, Papaioannou VE, McNamara JO. Null mutation of c-fos impairs structural and functional plasticities in the kindling model of epilepsy. J Neurosci. 1996;16:3827–3836. [PubMed: 8656277]
Stringer JL, Agarwal KS, Dure LS. Is cell death necessary for hippocampal mossy fiber sprouting. Epilepsy Res. 1997;27:67–76. [PubMed: 9169292]
Holmes GL, Gairsa J-L, Chevassus-Au-Lois N, Ben-Ari Y. Consequences of neonatal seizures in the rat: morphological and behavioral effects. Ann Neurol. 1998;44:845–857. [PubMed: 9851428]
Vaidya VA, Siuciak JA, Du F, Duman RS. Hippocampal mossy fiber sprouting induced by chronic electroconvulsive seizures. Neuroscience. 1999;89:157–166. [PubMed: 10051225]
Bender RA, Dubé C, Gonzalez-Vega R, Mina EW, Baram TZ. Mossy fiber plasticity and enhanced hippocampal excitability, without hippocampal cell loss or altered neurogenesis, in an animal model of prolonged febrile seizures. Hippocampus. 2003;13:399–412. [PMC free article: PMC2927853] [PubMed: 12722980]
Peterson GM, Ribak CE. Hippocampus of the seizure-sensitive gerbil is a specific site for anatomical changes in the GABAergic system. J Comp Neurol. 1987;261:405–422. [PubMed: 3611418]
Mathern GW, Bertram EH III, Babb TL, Pretorius JK, Kuhlman PA, Spradlin S, Mendoza D. In contrast to kindled seizures, the frequency of spontaneous epilepsy in the limbic status model correlates with greater aberrant fascia dentate excitatory and inhibitory axon sprouting, and increased staining for N-methyl-D-aspartate, AMPA and GABAA receptors. Neuroscience. 1997;77:1003–1019. [PubMed: 9130782]
Routbort MJ, Bausch SB, McNamara JO. Seizures, cell death, and mossy fiber sprouting in kainic acid-treated organotypic hippocampal cultures. Neuroscience. 1999;94:755–765. [PubMed: 10579566]
Zimmer J. Ipsilateral afferents to the commissural zone of the fascia dentate, demonstrated in decommissurated rats by silver impregnation. J Comp Neurol. 1971;142:393–416. [PubMed: 4106860]
Berger TW, Semple-Rowland S, Basset JL. Hippocampal polymorph neurons are the cells of origin for ipsilateral association and commissural afferents to the dentate gyrus. Brain Res. 1980;215:329–336. [PubMed: 6167320]
Buckmaster PS, Jongen-Rêlo AL. Highly specific neuron loss preserves lateral inhibitory circuits in the dentate gyrus of kainate-induced epileptic rats. J Neurosci. 1999;19:9519–9529. [PubMed: 10531454]
Austin JE, Buckmaster PS. Recurrent excitation of granule cells with basal dendrites and low interneuron density and inhibitory postsynaptic current frequency in the dentate gyrus of macaque monkeys. J Comp Neurol. 2004;476:205–218. [PubMed: 15269966]
Jiao Y, Nadler JV. Stereological analysis of GluR2-immunoreactive hilar neurons in the pilocarpine model of temporal lobe epilepsy: correlation of cell loss with mossy fiber sprouting. Exp Neurol. 2007;205:569–582. [PMC free article: PMC1995080] [PubMed: 17475251]
Buckmaster PS, Wenzel HJ, Kunkel DD, Schwartzkroin PA. Axon arbors and synaptic connections of hippocampal mossy cells in the rat in vivo. J Comp Neurol. 1996;366:270–292. [PubMed: 8698887]
Cavazos JE, Sutula TP. Progressive neuronal loss induced by kindling: a possible mechanism for mossy fiber synaptic reorganization and hippocampal sclerosis. Brain Res. 1990;527:1–6. [PubMed: 2282474]
Buckmaster PS, Dudek FE. Neuron loss, granule cell axon reorganization, and functional changes in the dentate gyrus of epileptic kainate-treated rats. J Comp Neurol. 1997;385:385–404. [PubMed: 9300766]
Gorter JA, van Vliet EA, Aronica E, Lopes da Silva FH. Progression of spontaneous seizures after status epilepticus is associated with mossy fibre sprouting and extensive bilateral loss of hilar parvalbumin and somatostatin-immunoreactive neurons. Eur J Neurosci. 2001;13:657–669. [PubMed: 11207801]
Nissinen J, Lukasiuk K, Pitkänen A. Is mossy fiber sprouting present at the time of the first spontaneous seizures in rat experimental temporal lobe epilepsy. Hippocampus. 2001;11:299–310. [PubMed: 11769311]
Silva JG, Mello LEAM. The role of mossy cell death and activation of protein synthesis in the sprouting of dentate mossy fibers: evidence from calretinin and neo-Timm staining in pilocarpine-epileptic mice. Epilepsia. 2000;41(suppl 6):S18–23. [PubMed: 10999514]
Rao MS, Hattiangady B, Reddy DS, Shetty AK. Hippocampal neurodegeneration, spontaneous seizures, and mossy fiber sprouting in the F344 rat model of temporal lobe epilepsy. J Neurosci Res. 2006;83:1088–1105. [PubMed: 16493685]
Nahm WK, Noebels JL. Nonobligate role of early or sustained expression of immediate-early gene proteins c-fos, c-jun, and zif/268 in hippocampal mossy fiber sprouting. J Neurosci. 1998;18:9245–9255. [PubMed: 9801364]
Zheng D, Butler LS, McNamara JO. Kindling and associated mossy fibre sprouting are not affected in mice deficient of NGFI-A/NGFI-B genes. Neuroscience. 1998;83:251–258. [PubMed: 9466414]
Meberg PJ, Gall CM, Routtenberg A. Induction of F1/GAP-43 gene: expression in hippocampal granule cells after seizures. Mol Brain Res. 1993;17:295–297. [PubMed: 8510501]
Bendotti C, Pende M, Sarmanin R. Expression of GAP-43 in the granule cells of rat hippocampus after seizure-induced sprouting of mossy fibres: in situ hybridization and immunocytochemical studies. Eur J Neurosci. 1994;6:509–515. [PubMed: 8025706]
Bendotti C, Pende M, Guglielmetti F, Sarmanin R. Cycloheximide inhibits kainic acid-induced GAP-43 mRNA in dentate granule cells in rats. NeuroReport. 1996;7:2539–2542. [PubMed: 8981419]
Cantallops I, Routtenberg A. Rapid induction by kainic acid of both axonal growth and F1/GAP-43 protein in the adult rat hippocampal granule cells. J Comp Neurol. 1996;366:303–319. [PubMed: 8698889]
Represa A, Pollard H, Moreau J, Ghilini G, Khrestchatisky M, Ben-Ari Y. Mossy fiber sprouting in epileptic rats is associated with a transient increased expression of α-tubulin. Neurosci Lett. 1993;156:149–152. [PubMed: 8414177]
Pollard H, Khrestchatisky M, Moreau J, Ben-Ari Y, Represa A. Correlation between reactive sprouting and microtubule protein expression in epileptic hippocampus. Neuroscience. 1994;61:773–787. [PubMed: 7838377]
Gall CM. Seizure-induced changes in neurotrophin expression: implications for epilepsy. Exp Neurol. 1993;124:150–166. [PubMed: 8282072]
Suzuki F, Junier M-P, Guilhem D, Sørensen J-C, Onteniente B. Morphogenetic effect of kainate on adult hippocampal neurons associated with a prolonged expression of brain-derived neurotrophic factor. Neuroscience. 1995;64:665–674. [PubMed: 7715779]
Guilhem D, Dreyfus PA, Makiura Y, Suzuki F, Onteniente B. Short increase of BDNF messenger RNA triggers kainic acid-induced neuronal hypertrophy in adult mice. Neuroscience. 1996;72:923–931. [PubMed: 8735220]
Danzer SC, Crooks KRC, Lo DC, McNamara JO. Increased expression of brain-derived neurotrophic factor induces formation of basal dendrites and axonal branching in dentate granule cells in hippocampal explant cultures. J Neurosci. 2002;22:9754–9763. [PubMed: 12427830]
Scharfman HE, Goodman JH, Sollas AL, Croll SD. Spontaneous limbic seizures after intrahippocampal infusion of brain-derived neurotrophic factor. Exp Neurol. 2002;174:201–214. [PubMed: 11922662]
Bender R, Heimrich B, Meyer M, Frotscher M. Hippocampal mossy fiber sprouting is not impaired in brain-derived neurotrophic factor-deficient mice. Exp Brain Res. 1998;120:399–402. [PubMed: 9628426]
Kokaia M, Ernfors P, Kokaia Z, Elmér E, Jaenisch R, Lindvall O. Suppressed epileptogenesis in BDNF mutant mice. Exp Neurol. 1995;133:215–224. [PubMed: 7649227]
Qiao X, Suri C, Knusel B, Noebels JL. Absence of hippocampal mossy fiber sprouting in transgenic mice overexpressing brain-derived neurotrophic factor. J Neurosci Res. 2001;64:268–276. [PubMed: 11319771]
Shetty AK, Zaman V, Shetty GA. Hippocampal neurotrophin levels in a kainate model of temporal lobe epilepsy: lack of correlation between brain-derived neurotrophic factor content and progression of aberrant dentate mossy fiber sprouting. J Neurochem. 2003;87:147–159. [PubMed: 12969262]
Koyama R, Yamada MK, Fujisawa S, Katoh-Semba R, Matsuki N, Ikegaya Y. Brain-derived neurotrophic factor induces hyperexcitable reentrant circuits in the dentate gyrus. J Neurosci. 2004;24:7215–7224. [PubMed: 15317847]
Niquet J, Jorquera I, Ben-Ari Y, Represa A. NCAM immunoreactivity on mossy fibers and reactive astrocytes in the hippocampus of epileptic rats. Brain Res. 1993;626:106–116. [PubMed: 8281421]
Mikkonen M, Soininen H, Kälviäinen R, Tapiola T, Ylinen A, Vapalahti M, Paljärvi L, Pitkänen A. Remodeling of neuronal circuitries in human temporal lobe epilepsy: increased expression of highly polysialylated neural cell adhesion molecular in the hippocampus and entorhinal cortex. Ann Neurol. 1998;44:923–934. [PubMed: 9851437]
Niquet J, Jorquera I, Faissner A, Ben-Ari Y, Represa A. Gliosis and axonal sprouting in the hippocampus of epileptic rats are associated with an increase of tenascin-C immunoreactivity. J Neurocytol. 1995;24:611–624. [PubMed: 7595669]
Holtmaat AJGD, Gorter JA, De Wit J, Tolner EA, Spijker S, Giger RJ, Lopes da Silva FH, Verhaagen J. Transient downregulation of Sema3A mRNA in a rat model for temporal lobe epilepsy. A novel molecular event potentially contributing to mossy fiber sprouting. Exp Neurol. 2003;182:142–150. [PubMed: 12821384]
Bausch SZ. Potential roles for hyaluronan and CD44 in kainic acid-induced mossy fiber sprouting in organotypic hippocampal slice cultures. Neuroscience. 2006;143:339–350. [PubMed: 16949761]
Mello LEAM, Cavalheiro EA, Tan AM, Kupfer WR, Pretorius JK, Babb TL, Finch DM. Circuit mechanisms of seizures in the pilocarpine model of chronic epilepsy: cell loss and mossy fiber sprouting. Epilepsia. 1993;34:985–995. [PubMed: 7694849]
Shetty AK, Zaman V, Hattiangady B. Repair of the injured adult hippocampus through graft-mediated modulation of the plasticity of the dentate gyrus in a rat model of temporal lobe epilepsy. J Neurosci. 2005;25:8391–8401. [PubMed: 16162921]
Isokawa M, Levesque MF, Babb TL, Engel JE Jr. Single mossy fiber axonal systems of human dentate granule cells studied in hippocampal slices from patients with temporal lobe epilepsy. J Neurosci. 1993;13:1511–1522. [PubMed: 8463831]
Sutula T, Zhang Z, Lynch M, Sayin U, Golarai G, Rod R. Synaptic and axonal remodeling of mossy fibers in the hilus and supragranular region of the dentate gyrus in kainate-treated rats. J Comp Neurol. 1998;390:578–594. [PubMed: 9450537]
Buckmaster PS, Dudek FE. In vivo intracellular analysis of granule cell axon reorganization in epileptic rats. J Neurophysiol. 1999;81:712–721. [PubMed: 10036272]
Wenzel HJ, Woolley CS, Robbins CA, Schwartzkroin PA. Kainic acid-induced mossy fiber sprouting and synapse formation in the dentate gyrus of rats. Hippocampus. 2000;10:244–260. [PubMed: 10902894]
Kobayashi M, Buckmaster PS. Reduced inhibition of dentate granule cells in a model of temporal lobe epilepsy. J Neurosci. 2003;23:2440–2452. [PubMed: 12657704]
Cameron HA, McKay RDG. Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J Comp Neurol. 2001;435:406–417. [PubMed: 11406822]
Parent JM, Yu TW, Leibowitz RT, Geschwind DH, Sloviter RS, Lowenstein DH. Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci. 1997;17:3727–3738. [PubMed: 9133393]
Bengzon J, Kokaia Z, Elmér E, Nanobashvili A, Kokaia M, Lindvall O. Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures. Proc Natl Acad Sci USA. 1997;94:10432–10437. [PMC free article: PMC23380] [PubMed: 9294228]
Parent JM, Tada E, Fike JR, Lowenstein DH. Inhibition of dentate granule cell neurogenesis with brain irradiation does not prevent seizure-induced mossy fiber synaptic reorganization in the rat. J Neurosci. 1999;19:4508–4519. [PubMed: 10341251]
Covolan L, Ribeiro LTC, Longo BM, Mello LEAM. Cell damage and neurogenesis in the dentate granule cell layer of adult rats after pilocarpine- or kainate-induced status epilepticus. Hippocampus. 2000;10:169–180. [PubMed: 10791839]
Jessberger S, Zhao C, Toni N, Clemenson GD Jr, Li Y, Gage FH. Seizure-associated, aberrant neurogenesis in adult rats characterized with retrovirus-mediated cell labeling. J Neurosci. 2007;27:9400–9407. [PubMed: 17728453]
Kron MM, Zhang H, Parent JM. The developmental stage of dentate granule cells dictates their contribution to seizure-induced plasticity. J Neurosci. 2010;30:2051–2059. [PubMed: 20147533]
Cavazos JE, Golarai G, Sutula TP. Mossy fiber synaptic reorganization induced by kindling: time course of development, progression, and permanence. J Neurosci. 1991;11:2795–2803. [PubMed: 1880549]
Swanson LW, Wyss JM, Cowan WM. An autoradiographic study of the organization of intrahippocampal association pathways in the rat. J Comp Neurol. 1978;181:681–716. [PubMed: 690280]
Thind KK, Yamawaki R, Phanwar I, Zhang G, Wen X, Buckmaster PS. Initial loss but later excess of GABAergic synapses with dentate granule cells in a rat model of temporal lobe epilepsy. J Comp Neurol. 2010;518:647–667. [PMC free article: PMC3098130] [PubMed: 20034063]
Buckmaster PS, Zhang GF, Yamawaki R. Axon sprouting in a model of temporal lobe epilepsy creates a predominantly excitatory feedback circuit. J Neurosci. 2002;22:6650–6658. [PubMed: 12151544]
Scharfman HE, Sollas AL, Berger RE, Goodman JH. Electrophysiological evidence of monosynaptic excitatory transmission between granule cells after seizure-induced mossy fiber sprouting. J Neurophysiol. 2003;90:2536–2547. [PubMed: 14534276]
Halabisky B, Parada I, Buckmaster PS, Prince DA. Excitatory input onto hilar somatostatin interneurons is increased in a chronic model of epilepsy. J Neurophysiol. 2010;104:2214–2233. [PMC free article: PMC3774571] [PubMed: 20631216]
Represa A, Le Gal La, Salle G, Ben-Ari Y. Hippocampal plasticity in the kindling model of epilepsy in rats. Neurosci Lett. 1989;99:345–350. [PubMed: 2542847]
Dashtipour K, Tran PH, Okazaki MM, Nadler JV, Ribak CE. Ultrastructural features and synaptic connections of hilar ectopic granule cells in the rat dentate gyrus are different from those of granule cells in the granule cell layer. Brain Res. 2001;890:261–271. [PubMed: 11164792]
Pierce JP, Melton J, Punsoni M, McCloskey DP, Scharfman HE. Mossy fibers are the primary source of afferent input to ectopic granule cells that are born after pilocarpine-induced seizures. Exp Neurol. 2005;196:316–331. [PMC free article: PMC1431686] [PubMed: 16342370]
Franck JE, Pokorny J, Kunkel DD, Schwartzkroin PA. Physiologic and morphologic characteristics of granule cell circuitry in human epileptic hippocampus. Epilepsia. 1995;36:543–558. [PubMed: 7555966]
Ribak CE, Tran PH, Spigelman I, Okazaki MM, Nadler JV. Status epilepticus-induced hilar basal dendrites on rodent granule cells contribute to recurrent excitatory circuitry. J Comp Neurol. 2000;428:240–253. [PubMed: 11064364]
Cavazos JE, Zhang P, Qazi R, Sutula TP. Ultrastructural features of sprouted mossy fiber synapses in kindled and kainic acid-treated rats. J Comp Neurol. 2003;458:272–292. [PubMed: 12619081]
Represa A, Jorquera I, Le Gal La, Salle G, Ben-Ari Y. Epilepsy induced collateral sprouting of hippocampal mossy fibers: does it induce the development of ectopic synapses with granule cell dendrites. Hippocampus. 1993;3:257–268. [PubMed: 8353609]
Zhang N, Houser CR. Ultrastructural localization of dynorphin in the dentate gyrus in human temporal lobe epilepsy: a study of reorganized mossy fiber synapses. J Comp Neurol. 1999;405:472–490. [PubMed: 10098940]
Patel LS, Wenzel HJ, Schwartzkroin PA. Physiological and morphological characterization of dentate granule cells in the p35 knock-out mouse hippocampus: evidence for an epileptic circuit. J Neurosci. 2004;34:9005–9014. [PubMed: 15483119]
Nusser Z, Lujan R, Laube G, Roberts JDB, Molnar E, Somogyi P. Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus. Neuron. 1998;21:545–559. [PubMed: 9768841]
Ganeshina O, Berry RW, Petralia RS, Nicholson DA, Geinesman Y. Differences in the expression of AMPA and NMDA receptors between axospinous perforated and nonperforated synapses are related to the configuration and size of postsynaptic densities. J Comp Neurol. 2004;468:86–95. [PubMed: 14648692]
Kotti T, Riekkinen PJ, Miettinen R. Characterization of target cells for aberrant mossy fiber collaterals in the dentate gyrus of epileptic rat. Exp Neurol. 1997;146:323–330. [PubMed: 9270041]
Sloviter RS, Zappone CA, Harvey BD, Frotscher M. Kainic acid-induced recurrent mossy fiber innervation of dentate gyrus inhibitory interneurons: possible anatomical substrate of granule cell hyperinhibition in chronically epileptic rats. J Comp Neurol. 2006;494:944–960. [PMC free article: PMC2597112] [PubMed: 16385488]
Blasco-Ibánez JM, Martinez-Guijarro FJ, Freund TF. Recurrent mossy fibers preferentially innervate parvalbumin-immunoreactive interneurons in the granule cell layer of the rat dentate gyrus. NeuroReport. 2000;11:3219–3225. [PubMed: 11043552]
Buhl EH, Otis TS, Mody I. Zinc-induced collapse of augmented inhibition by GABA in a temporal lobe epilepsy model. Science. 1996;271:369–373. [PubMed: 8553076]
Zhang W, Buckmaster PS. Dysfunction of the dentate basket cell circuit in a rat model of temporal lobe epilepsy. J Neurosci. 2009;29:7846–7856. [PMC free article: PMC2838908] [PubMed: 19535596]
Golarai G, Sutula TP. Functional alterations in the dentate gyrus after induction of long-term potentiation, kindling, and mossy fiber sprouting. J Neurophysiol. 1996;75:343–353. [PubMed: 8822562]
Buckmaster PS, Dudek FE. Network properties of the dentate gyrus in epileptic rats with hilar neuron loss and granule cell axon reorganization. J Neurophysiol. 1997;77:2685–2696. [PubMed: 9163384]
Cronin J, Obenaus A, Houser CR, Dudek FE. Electrophysiology of dentate granule cells after kainate-induced synaptic reorganization of the mossy fibers. Brain Res. 1992;573:305–310. [PubMed: 1504768]
Tauck DL, Nadler JV. Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acid-treated rats. J Neurosci. 1985;5:1016–1022. [PubMed: 3981241]
Hardison JL, Okazaki MM, Nadler JV. Modest increase in extracellular potassium unmasks effect of recurrent mossy fiber growth. J Neurophysiol. 2000;84:2380–2389. [PubMed: 11067980]
Otsu Y, Maru E, Ohata H, Takashima I, Kajiwara R, Iijima T. Optical recording study of granule cell activities in the hippocampal dentate gyrus of kainate-treated rats. J Neurophysiol. 2000;83:2421–2430. [PubMed: 10758143]
Wuarin J-P, Dudek FE. Electrographic seizures and new recurrent excitatory circuits in the dentate gyrus of hippocampal slices from kainate-treated epileptic rats. J Neurosci. 1996;16:4438–4448. [PubMed: 8699254]
Wuarin J-P, Dudek FE. Excitatory synaptic input to granule cells increases with time after kainate treatment. J Neurophysiol. 2001;85:1067–1077. [PubMed: 11247977]
Molnár P, Nadler JV. Mossy fiber--granule cell synapses in the normal and epileptic rat dentate gyrus studied with minimal laser photostimulation. J Neurophysiol. 1999;82:1883–1894. [PubMed: 10515977]
Lynch M, Sutula T. Recurrent excitatory connectivity in the dentate gyrus of kindled and kainic acid-treated rats. J Neurophysiol. 2000;83:693–704. [PubMed: 10669485]
Miles R, Wong RKS. Excitatory synaptic interactions between CA3 neurones in the guinea-pig hippocampus. J Physiol. 1986;373:397–418. [PMC free article: PMC1182545] [PubMed: 3018233]
Feng L, Molnár P, Nadler JV. Short-term frequency-dependent plasticity at recurrent mossy fiber synapses of the epileptic brain. J Neurosci. 2003;23:5381–5390. [PubMed: 12832564]
Epsztein J, Represa A, Jorquera I, Ben-Ari Y, Crépel V. Recurrent mossy fibers establish aberrant kainate receptor-operated synapses on granule cells from epileptic rats. J Neurosci. 2005;25:8229–8239. [PubMed: 16148230]
Simmons ML, Terman GW, Chavkin C. Spontaneous excitatory currents and κ-opioid receptor inhibition in dentate gyrus are increased in the rat pilocarpine model of temporal lobe epilepsy. J Neurophysiol. 1997;7:1860–1868. [PubMed: 9325355]
Sloviter RS. Possible functional consequences of synaptic reorganization in the dentate gyrus of kainate-treated rats. Neurosci Lett. 1992;137:91–96. [PubMed: 1625822]
Tu B, Timofeeva O, Jiao Y, Nadler JV. Spontaneous release of neuropeptide Y tonically inhibits recurrent mossy fiber synaptic transmission in epileptic brain. J Neurosci. 2005;25:1718–1729. [PubMed: 15716408]
Schwarzer C, Sperk G. Hippocampal granule cells express glutamic acid decarboxylase-67 after limbic seizures in the rat. Neuroscience. 1995;69:705–709. [PubMed: 8596641]
Gloor P. The temporal lobe and limbic system. New York: Oxford University Press; 1997. pp. 677–691.
Elmér E, Kokaia Z, Kokaia M, Lindvall O, McIntyre DC. Mossy fibre sprouting: evidence against a facilitatory role in epileptogenesis. NeuroReport. 1997;8:1193–1196. [PubMed: 9175112]
Armitage LL, Mohapel P, Jenkins EM, Hannesson DK, Corcoran ME. Dissociation between mossy fiber sprouting and rapid kindling with low-frequency stimulation of the amygdala. Brain Res. 1998;781:37–44. [PubMed: 9507059]
Sayin U, Osting S, Hagen J, Rutecki P, Sutula T. Spontaneous seizures and loss of axo-axonic and axo-somatic inhibition induced by repeated brief seizures in kindled rats. J Neurosci. 2003;23:2759–2768. [PubMed: 12684462]
Lytton WW, Hellman KM, Sutula TP. Computer models of hippocampal circuit changes of the kindling model of epilepsy. Arti Intell Med. 1998;13:81–97. [PubMed: 9654380]
Santhakumar V, Aradi I, Soltesz I. Role of mossy fiber sprouting and mossy cell loss in hyperexcitability: a network model of the dentate gyrus incorporating cell types and axonal topography. J Neurophysiol. 2005;93:437–453. [PubMed: 15342722]
Dyhrfjeld-Johnsen J, Santhakumar V, Morgan RJ, Huerta R, Tsimring L, Soltesz I. Topological determinants of epileptogenesis in large-scale structural and functional models of the dentate gyrus derived from experimental data. J Neurophysiol. 2007;97:1566–1587. [PubMed: 17093119]
Morgan RJ, Soltesz I. Nonrandom connectivity of the epileptic dentate gyrus predicts a major role for neuronal hubs in seizures. Proc Natl Acad Sci USA. 2008;105:6179–6184. [PMC free article: PMC2299224] [PubMed: 18375756]
Bausch SZ, McNamara JO. Contributions of mossy fiber and CA1 pyramidal cell sprouting to dentate granule cell hyperexcitability in kainic acid-treated hippocampal slice cultures. J Neurophysiol. 2004;92:3582–3595. [PubMed: 15269228]
Gabriel S, Njunting M, Pomper JK, Merschhemke M, Sanabria ERG, Eilers A, Kivi A, Zeller M, Meencke H-J, Cavalheiro EA, Heinemann U, Lehmann TN. Stimulus and potassium-induced epileptiform activity in the human dentate gyrus from patients with and without hippocampal sclerosis. J Neurosci. 2004;24:10416–10430. [PubMed: 15548657]
Patrylo PR, Dudek FE. Physiological unmasking of new glutamatergic pathways in the dentate gyrus of hippocampal slices form kainate-induced epileptic rats. J Neurophysiol. 1998;79:418–429. [PubMed: 9425210]
Winokur RS, Kubal T, Liu D, Davis SF, Smith BN. Recurrent excitation in the dentate gyrus of a murine model of temporal lobe epilepsy. Epilepsy Res. 2004;48:93–105. [PubMed: 15120741]
Lemos T, Cavalheiro EA. Suppression of pilocarpine-induced status epilepticus and the late development of epilepsy in rats. Exp Brain Res. 1995;102:423–428. [PubMed: 7737389]
Mathern GW, Cifuentes F, Leite JP, Pretorius JK, Babb TL. Hippocampal EEG excitability and chronic spontaneous seizures are associated with aberrant synaptic reorganization in the rat intrahippocampal kainate model. EEG Clin Neurophysiol. 1993;87:326–339. [PubMed: 7693444]
Pitkänen A, Kharatishvili I, Narkilahti S, Lukasiuk K, Nissinen J. Administration of diazepam during status epilepticus reduces development and severity of epilepsy in rat. Epilepsy Res. 2005;63:27–42. [PubMed: 15716080]
Kharatishvili I, Nissinen JP, McIntosh TK, Pitkänen A. A model of posttraumatic epilepsy induced by lateral fluid-percussion brain injury in rats. Neuroscience. 2006;140:685–697. [PubMed: 16650603]
Cronin J, Dudek FE. Chronic seizures and collateral sprouting of dentate mossy fibers after kainic acid treatment in rats. Brain Res. 1988;474:181–184. [PubMed: 3214710]
Timofeeva OA, Peterson GM. Dissociation of mossy fiber sprouting and electrically-induced seizure sensitivity: rapid kindling versus adaptation. Epilepsy Res. 1999;33:99–115. [PubMed: 10094422]
Spencer SS, Kim J, de Lanerolle N, Spencer DD. Differential neuronal and glial relations with parameters of ictal discharge in mesial temporal lobe epilepsy. Epilepsia. 1999;40:708–712. [PubMed: 10368067]
Pitkänen A, Nissinen J, Lukasiuk K, Jutila L, Paljärvi L, Salmenperä T, Karkola K, Vapalahti M, Ylinen A. Association between the density of mossy fiber sprouting and seizure frequency in experimental and human temporal lobe epilepsy. Epilepsia. 2000;41(suppl 6):S24–29. [PubMed: 10999515]
Wenzel HJ, Born DE, Dubach MF, Gundersen VM, Maravilla KR, Robbins CA, Szot P, Zierath D, Schwartzkroin PA. Morphological plasticity in an infant monkey model of temporal lobe epilepsy. Epilepsia. 2000;41(suppl 6):S70–75. [PubMed: 10999523]
Lehmann T-N, Gabriel S, Eilers A, Njunting M, Kovacs R, Schulze K, Lanksch WR, Heinemann U. Fluorescent tracer in pilocarpine-treated rats shows widespread aberrant hippocampal neuronal connectivity. Eur J Neurosci. 2001;14:83–95. [PubMed: 11488952]
Zhang X, Cui S-S, Wallace AE, Hannesson DK, Schmued LC, Saucier DM, Honer WG, Corcoran ME. Relations between brain pathology and temporal lobe epilepsy. J Neurosci. 2002;22:6052–6061. [PubMed: 12122066]
Raol VSH, Budreck EC, Brooks-Kayal AR. Epilepsy after early-life seizures can be independent of hippocampal injury. Ann Neurol. 2003;53:503–511. [PubMed: 12666118]
Jung K-H, Chu K, Kim M, Jeong S-W, Song Y-M, Lee S-T, Kim J-Y, Lee SK, Roh JK. Continuous cytosine-b-D-arabinofuranoside infusion reduces ectopic granule cells in adult rat hippocampus with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Eur J Neurosci. 2004;9:3219–3226. [PubMed: 15217378]
Williams PA, Dou P, Dudek FE. Epilepsy and synaptic reorganization in a perinatal rat model of hypoxia-ischemia. Epilepsia. 2004;45:1210–1218. [PubMed: 15461675]
Harvey BD, Sloviter RS. Hippocampal granule cell activity and c-fos expression during spontaneous seizures in awake, chronically epileptic, pilocarpine-treated rats: implications for hippocampal epileptogenesis. J Comp Neurol. 2005;488:442–463. [PubMed: 15973680]
Kadam SD, Dudek FE. Neuropathological features of a rat model for perinatal hypoxic-ischemic encephalopathy with associated epilepsy. J Comp Neurol. 2007;505:716–737. [PMC free article: PMC4607042] [PubMed: 17948865]
Holtzman DM, Lowenstein DH. Selective inhibition of axon outgrowth by antibodies to NGF in a model of temporal lobe epilepsy. J Neurosci. 1995;15:7062–7070. [PubMed: 7472461]
Pitkänen A, Nissinen J, Jolkkonen E, Tuunanen J, Halonen T. Effects of vigabatrin treatment on status epilepticus-induced neuronal damage and mossy fiber sprouting in the rat hippocampus. Epilepsy Res. 1999;33:67–85. [PubMed: 10022367]
Buckmaster PS. Chronic infusion of tetrodotoxin does not block mossy fiber sprouting in pilocarpine-treated rats. Epilepsia. 2004;45:452–458. [PubMed: 15101826]
Longo BM, Mello LEAM. Blockade of pilocarpine- or kainate-induced mossy fiber sprouting by cycloheximide does not prevent subsequent epileptogenesis in rats. Neurosci Lett. 1997;226:163–166. [PubMed: 9175592]
Longo BM, Mello LEAM. Supragranular mossy fiber sprouting is not necessary for spontaneous seizures in the intrahippocampal kainate model of epilepsy in the rat. Epilepsy Res. 1998;32:172–182. [PubMed: 9761318]
Schreiber SS, Tocco G, Najm I, Thompson RF, Baudry M. Cycloheximide prevents kainate-induced neuronal death and c-fos expression in adult rat brain. J Mole Neurosci. 1993;4:149–159. [PubMed: 8292488]
Longo BM, Covolan L, Chadi G, Mello LEAM. Sprouting of mossy fibers and the vacating of postsynaptic targets in the inner molecular layer of the dentate gyrus. Exp Neurol. 2003;181:57–67. [PubMed: 12710934]
Williams PA, Wuarin J-P, Dou P, Ferraro DJ, Dudek FE. Reassessment of the effects of cycloheximide on mossy fiber sprouting and epileptogenesis in the pilocarpine model of temporal lobe epilepsy. J Neurophysiol. 2002;88:2075–2087. [PubMed: 12364529]
Toyoda I, Buckmaster PS. Prolonged infusion of cycloheximide does not block mossy fiber sprouting in a model of temporal lobe epilepsy. Epilepsia. 2005;46:1017–1020. [PubMed: 16026553]
Ikegaya Y, Nishiyama N, Matsuki N. L-type Ca2+ channel blocker inhibits mossy fiber sprouting and cognitive deficits following pilocarpine seizures in immature mice. Neuroscience. 2000;98:647–659. [PubMed: 10891608]
Moia LJMP, Matsui H, de Barros GAM, Tomizawa K, Miyamoto K, Kuwata Y, Tokuda M, Itano T, Hatase O. Immunosuppressants and calcineurin inhibitors, cyclosporin A and FK506, reversibly inhibit epileptogenesis in amygdaloid kindled rat. Brain Res. 1994;648:337–341. [PubMed: 7522929]
Moriwaki A, Lu Y-F, Hayashi Y, Tomizawa K, Tokuda M, Itano T, Hatase O, Matsui H. Immunosuppressant FK506 prevents mossy fiber sprouting induced by kindling stimulation. Neurosci Res. 1996;25:191–194. [PubMed: 8829156]
Ingram EA, Toyoda I, Wen X, Buckmaster PS. Prolonged infusion of inhibitors of calcineurin or L-type calcium channels does not block mossy fiber sprouting in a model of temporal lobe epilepsy. Epilepsia. 2009;50:56–64. [PMC free article: PMC3007596] [PubMed: 18616558]
Muller-Schwarze AB, Tandon P, Liu Z, Yang Y, Stafstrom CE. Ketogenic diet reduces spontaneous seizures and mossy fiber sprouting in the kainic acid model. NeuroReport. 1999;10:1517–1522. [PubMed: 10380973]
Cadotte DW, Xu B, Racine RJ, MacQueen GM, Wang JF, McEwen B, Young LT. Chronic lithium treatment inhibits pilocarpine-induced mossy fiber sprouting in rat hippocampus. Neuropsychopharmacology. 2003;28:1448–1453. [PubMed: 12784117]
Wang X-M, Bausch SB. Effects of distinct classes of N-methyl-D-aspartate receptor antagonists on seizures, axonal sprouting and neuronal loss in vitro: suppression by NR2B-selective antagonists. Neuropharmacology. 2004;47:1008–1020. [PubMed: 15555635]
Zeng L-H, Rensing NR, Wong M. The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J Neurosci. 2009;29:6964–6972. [PMC free article: PMC2727061] [PubMed: 19474323]
Buckmaster PS, Ingram EA, Wen X. Inhibition of the mammalian target of rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy. J Neurosci. 2009;29:8259–8269. [PMC free article: PMC2819377] [PubMed: 19553465]
Harris TE, Lawrence JC Jr. TOR signaling. Sci STKE. 2003:re15. [PubMed: 14668532]
Swiech L, Perycz M, Malik A, Jaworski J. Role of mTOR in physiology and pathology of the nervous system. Biochem Biophys Acta. 2008;1784:116–132. [PubMed: 17913600]
Buckmaster PS, Lew FH. Rapamycin suppresses mossy fiber sprouting but not seizure frequency in a mouse model of temporal lobe epilepsy. J Neurosci. 2011;31:2337–2347. [PMC free article: PMC3073836] [PubMed: 21307269]
Huang X, Zhang H, Yang J, Wu J, McMahon J, Lin Y, Cao Z, Gruenthal M, Huang Y. Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy. Neurobiol Dis. 2010;40:193–199. [PMC free article: PMC2926303] [PubMed: 20566381]
McKinney RA, Debanne D, Gähwiler BH, Thompson SM. Lesion-induced axonal sprouting and hyperexcitability in the hippocampus in vitro: implications for the genesis of posttraumatic epilepsy. Nat Med. 1997;3:990–996. [PubMed: 9288725]
Siddiqui AH, Joseph SA. CA3 axonal sprouting in kainate-induced chronic epilepsy. Brain Res. 2005;1066:129–146. [PubMed: 16359649]
Perez Y, Morin F, Beaulieu C, Lacaille JC. Axonal sprouting of CA1 pyramidal cells in hyperexcitable hippocampal slices of kainate-treated rats. Eur J Neurosci. 1996;8:736–748. [PubMed: 9081625]
Salin P, Tseng G-F, Hoffman S, Parada I, Prince DA. Axonal sprouting in layer V pyramidal neurons of chronically injured cerebral cortex. J Neurosci. 1995;15:8234–8245. [PubMed: 8613757]
Represa A, Robain O, Tremblay E, Ben-Ari Y. Hippocampal plasticity in childhood epilepsy. Neurosci Lett. 1989;99:351–355. [PubMed: 2542848]
Suzuki F, Makiura Y, Guilhem D, Sørensen J-C, Onteniente B. Correlated axonal sprouting and dendritic spine formation during kainate-induced neuronal morphogenesis in the dentate gyrus of adult mice. Exp Neurol. 1997;145:203–213. [PubMed: 9184122]
Thomas AM, Corona-Morales AA, Ferraguti F, Capogna M. Sprouting of mossy fibers and presynaptic inhibition by group II metabotropic glutamate receptors in pilocarpine-treated rat hippocampal slice cultures. Neuroscience. 2005;131:303–320. [PubMed: 15708475]
Bernard PB, MacDonald DS, Gill DA, Ryan CL, Tasker RA. Hippocampal mossy fiber sprouting and elevated trkB receptor expression following systemic administration of low dose domoic acid during neonatal development. Hippocampus. 2007;17:1121–1133. [PubMed: 17636548]
Ribak CE, Seress L, Weber P, Epstein CM, Henry TR, Bakay RAE. Alumina gel injections into the temporal lobe of rhesus monkeys cause complex partial seizures and morphological changes found in human temporal lobe epilepsy. J Comp Neurol. 1998;401:266–290. [PubMed: 9822153]
Gunderson VM, Dubach M, Szot P, Born DE, Wenzel HJ, Maravilla KR, Zierath DK, Robbins CA, Schwartzkroin PA. Development of a model of status epilepticus in pigtailed macaque infant monkeys. Dev Neurosci. 1999;21:352–364. [PubMed: 10575259]
Golarai G, Cavazos JE, Sutula TP. Activation of the dentate gyrus by pentylenetetrazol evoked seizures induces mossy fiber synaptic reorganization. Brain Res. 1992;593:257–264. [PubMed: 1450933]
Garcia-Cairasco N, Wakamatsu H, Oliveira JAC, Gomes ELT, Del Bel EA, Mello LEAM. Neuroethological and morphological (neo-Timm staining) correlates of limbic recruitment during the development of audiogenic kindling in seizure susceptible Wistar rats. Epilepsy Res. 1996;26:177–192. [PubMed: 8985699]
Stanfield BB. Excessive intra- and supragranular mossy fibers in the dentate gyrus of tottering (tg/tg) mice. Brain Res. 1989;480:294–299. [PubMed: 2713655]
Colling SB, Khana M, Collinge J, Jefferys JG. Mossy fibre reorganization in the hippocampus of prion protein null mice. Brain Res. 1997;755:28–35. [PubMed: 9163538]
Amano S, Ikeda M, Uemura S, Fukuoka J, Tsuji A, Sasahara M, Hayase Y, Hazama F. Mossy fiber sprouting in the dentate gyrus in a newly developed epileptic mutant, Ihara epileptic rat. Brain Res. 1999;834:214–218. [PubMed: 10407119]
Wenzel HJ, Robbins CA, Tsai L-H, Schwartzkroin PA. Abnormal morphological and functional organization of the hippocampus in a p35 mutant model of cortical dysplasia associated with spontaneous seizures. J Neurosci. 2001;21:983–998. [PubMed: 11157084]
Böhm D, Schwegler H, Kotthaus L, Nayernia K, Rickmann M, Köhler M, Rosenbusch J, Engel W, Flügge G, Burfeind P. Disruption of PLC-β1-mediated signal transduction in mutant mice causes age-dependent hippocampal mossy fiber sprouting and neurodegeneration. Mol Cell Neurosci. 2002;21:584–601. [PubMed: 12504592]
Mitchell TW, Buckmaster PS, Hoover EA, Whalen LR, Dudek FE. Neuron loss and axon reorganization in the dentate gyrus of cats infected with feline immunodeficiency virus. J Comp Neurol. 1999;411:563–577. [PubMed: 10421868]
Chen S-F, Huang C-C, Wu H-M, Chen S-H, Liang Y-C, Ksu KS. Seizure, neuron loss, and mossy fiber sprouting in herpes simplex virus type 1-infected organotypic hippocampal cultures. Epilepsia. 2004;45:322–332. [PubMed: 15030494]
Hannesson DK, Armitage LL, Mohapel P, Corcoran ME. Time course of mossy fiber sprouting following bilateral transection of the fimbria/fornix. NeuroReport. 1997;8:2299–2303. [PubMed: 9243629]
Coltman BW, Earley EM, Shahar A, Dudek FE, Ide CF. Factors influencing mossy fiber collateral sprouting in organotypic slice cultures of neonatal mouse hippocampus. J Comp Neurol. 1995;362:209–222. [PubMed: 8576434]
Onodera H, Aoki H, Yae T, Kogure K. Post-ischemic synaptic plasticity in the rat hippocampus after long-term survival: histochemical and autoradiographic study. Neuroscience. 1990;38:125–136. [PubMed: 1701523]
Golarai G, Greenwood AC, Feeney DM, Connor JA. Physiological and structural evidence for hippocampal involvement in persistent seizure susceptibility after traumatic brain injury. J Neurosci. 2001;21:8523–8537. [PubMed: 11606641]
Santhakumar V, Ratzliff ADH, Jeng J, Toth Z, Soltesz I. Long-term hyperexcitability in the hippocampus after experimental head trauma. Ann Neurol. 2001;50:708–717. [PubMed: 11761468]
Anderson AE, Hrachoby RA, Antalffy BA, Armstrong DL, Swann JW. A chronic focal epilepsy with mossy fiber sprouting follows recurrent seizures induced by intrahippocampal tetanus toxin injection in infant rats. Neuroscience. 1999;92:73–82. [PubMed: 10392831]
Mitchell J, Gatherer M, Sundstrom LE. Aberrant Timm-stained fibres in the dentate gyrus following tetanus toxin-induced seizures in the rat. Neuropathol Appl Neurobiol. 1996;22:129–135. [PubMed: 8732188]
Sandoval MRL, Lebrun I. TsTx toxin isolated from Tityus serrulatus scorpion venom induces spontaneous recurrent seizures and mossy fiber sprouting. Epilepsia. 2003;44:904–911. [PubMed: 12823572]
Copyright © 2012, Michael A Rogawski, Antonio V Delgado-Escueta, Jeffrey L Noebels, Massimo Avoli and Richard W Olsen.

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