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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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Seizure-induced formation of basal dendrites on granule cells of the rodent dentate gyrus

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Status epilepticus results in several neuroplastic changes to the granule cells of the hippocampal dentate gyrus. These include mossy fiber sprouting, granule cell dispersion, hilar ectopic granule cells and hilar basal dendrites. This chapter reviews the seizure-induced formation of hilar basal dendrites on granule cells in rodents. This aberrant structural change is associated with a new, predominantly excitatory input to granule cells and more excitatory interconnections between granule cells – i.e., a new pathway in addition to that arising from sprouted mossy fibers in the inner molecular layer. Hilar basal dendrites are found on newly generated dentate granule cells; significant increases in the frequency of newly generated granule cells with hilar basal dendrites are found within one day after seizures are induced. The development of hilar basal dendrites on granule cells occurs rapidly after seizures; their persistence may be due to the rapidly forming synapses that integrate these newly-generated granule cells into synaptic circuitry. The basal dendrites appear to use hypertrophied astrocytic processes as guides for growth into the hilus. These data provide insight into anatomical and functional plasticity of rodent granule cells following seizures. The role that these basal dendrites play in the development of spontaneous seizures has yet to be determined.

Granule cells of the normal adult rodent dentate gyrus generally have the typical morphology of bipolar cells. Their apical dendrites arise from one pole and arborize into the molecular layer, while the axon originates from the base of the granule cell body and extends into the hilus subjacent to the granule cell layer.1 Two exceptions to this rule have been observed. Sometimes recurrent basal dendrites arise from the base of granule cell bodies and then curve back through the granule cell layer in the direction of the molecular layer where they join apical dendrites.2–4 Despite this unusual origination, dendrites of dentate granule cells in rodents arborize exclusively in the molecular layer. The other exception is the rare instance of an axon originating from the granule cell’s apical dendrite or the apical pole of its cell body.4 In this instance, the axon descends into the hilus without giving rise to collaterals. Both of these morphologies suggest that rat granule cells are more heterogeneous than previously indicated.

Dentate granule cells from humans and non-human primates differ from granule cells from rodents; primate granule cells commonly have basal dendrites. Seress and Mrzljak5 were the first to show that primate granule cells display basal dendrites in normal brain. Other studies confirmed this observation and showed many granule cells in monkey have basal dendrites that enter the hilus.6 These basal dendrites have large complex spines and smaller, “stubby” spines. About 10% of granule cells in the monkey dentate gyrus exhibit basal dendrites. Pertinent to this review is the finding that greater numbers of granule cells with hilar basal dendrites are found in the temporal lobes of epileptic humans as compared to normal human control tissues.7,8 The remainder of this chapter will focus on the seizure-induced formation of hilar basal dendrites in rodents, and the potential significance of hilar basal dendrites in epileptogenesis.


Seizure-induced hilar basal dendrites on dentate granule cells have been observed in the brains of epileptic animals (Figure 1). Using rats in which the perforant path was stimulated to cause seizures, Spigelman et al.9 showed that 6–15% of Golgi-impregnated granule cells had basal dendrites that extended into the hilus. In contrast, basal dendrites were not observed in control animals. The presence of basal dendrites on dentate granule cells in the kainic acid model of temporal lobe epilepsy was described shortly afterwards by Buckmaster and Dudek.10 A subsequent study of rats with pilocarpine-induced seizures provided evidence for basal dendrites on dentate granule cells in yet another model of epilepsy.3 Therefore, in three unique models of temporal lobe epilepsy, anatomical studies demonstrate the formation of basal dendrites on granule cells of the dentate gyrus. In addition, rats with amygdala kindling also have granule cells with hilar basal dendrites.11 Therefore, it is reasonable to assume that hilar basal dendrites in rats form after both seizures and excessive neuronal activity within the limbic system.

Figure 1. Light (A.B,C) and Electron (D,E) micrographs of hilar basal dendrites.

Figure 1

Light (A.B,C) and Electron (D,E) micrographs of hilar basal dendrites. As can be seen in the light micrograph (A,B,C), the basal side of the neuron(arrows) has a dendritic process which extends into the deep hilus. In D, a labeled basal dendrite (BD) (more...)

The basal dendrites observed on granule cells from epileptic rats were densely packed with spines along their length, and these spines were similar in morphology to those found on the apical dendrites of granule cells.9 These dendrites commonly originated from the base of the granule cell body (on the hilar side) and could be clearly distinguished from the axon initial segment.3 It was rare for the basal dendrite to arise from the lateral side of the granule cell body or the apical dendrite.9 These basal dendrites run horizontally beneath the granule cell layer or extend relatively straight into the hilus, perpendicular to the granule cell layer. The basal dendrites either branch or remained unbranched. Their lengths vary between 200–500 μm, and the basal dendrites populate the subgranular region of the hilus (previously defined as the first 50 μm subjacent to the granule cell layer). Most of the granule cells with basal dendrites had cell bodies located at the hilar border of the granule cell layer or within one or two cell bodies away from this border.

Using electron microscopy, hilar basal dendrites were analyzed in hippocampal slices following biocytin injections into the stratum lucidum of CA3 to retrogradely label the projecting granule cells.3 Granule cells at the border of the hilus had spiny dendrites projecting into the hilus. Both the spines and dendritic shafts of these biocytin-labeled basal dendrites were postsynaptic to axon terminals (Figure 1). The fact that some of the labeled spines and dendrites were postsynaptic to small, biocytin-labeled axon terminals3 suggested that the granule cells with basal dendrites participated in synaptic circuitry with mossy fiber synapses derived from other dentate granule cells. Subsequent electron microscopic analysis revealed that less than 10% of the synapses on seizure-induced basal dendrites were GABAergic; the great majority appeared to be excitatory.12 These electron microscopic data support the view that the synapses on basal dendrites of granule cells from epileptic animals are likely involved in additional excitatory feedback circuits that could play a role in seizure propensity.


Granule cell basal dendrites are observed in temporal lobe epilepsy,3,9,10 other pathophysiological conditions,13 and normally (to a variable extent) in primates.6 The functional consequences of this special subpopulation of granule cells depend largely on the synaptic inputs received by basal dendrites and how those inputs differ from those of granule cells with only apical dendrites. Available evidence indicates that basal dendrites primarily receive excitatory input from neighboring granule cells, and this input establishes a recurrent excitatory positive-feedback circuit.3,12 Basal dendrite involvement in additional circuits has been shown or is suspected, but many questions remain.


Ultrastructural evidence has been used to characterize excitatory synapses onto basal dendrites.3,12,14–16 Ribak et al.3 were first to demonstrate that granule cell axons (mossy fibers) are at least one source of excitatory synaptic input onto basal dendrites. Mossy fiber synapses with basal dendrites were identified later in epileptic p35 knockout mice.17 Mossy fiber synapses with basal dendrites create a monosynaptic and local positive-feedback circuit among granule cells. The aberrant circuit is local (and constrained along the septotemporal axis) because mossy fibers remain close to their granule cell of origin, even in epileptic animals with mossy fiber sprouting.10 Since mossy fibers are concentrated in the hilus, they probably account for a substantial fraction of excitatory synaptic input to basal dendrites. In addition, mossy fibers from epileptic pilocarpine-treated rats are the major source of excitatory synapses to apical dendrites and somata of hilar ectopic granule cells.18,19

Widespread convergence of excitatory connections onto hilar basal dendrites might contribute to seizure activity in epileptic animals. For example, other glutamatergic neurons, including mossy cells and CA3 pyramidal cells, extend their axons into the hilus20 where they may synapse with basal dendrites. Normally in control animals, mossy cells and CA3 pyramidal cells are directly and strongly excited by granule cells. Mossy cells, in turn, project their axons into the inner molecular layer where they synapse with granule cell apical dendrites.21,22 To a lesser extent, some CA3 pyramidal cells also extend axons into the inner molecular layer,23,24 and likely synapse with granule cell apical dendrites. Disynaptic recurrent excitation to granule cells might be exaggerated in epileptic animals because of axonal sprouting by the surviving mossy cells and CA3 pyramidal cells25 and the formation of new synapses between these aberrant axon collaterals with basal dendrites.

Computational models can provide additional confirmation of the significance of increased excitatory drive due to basal dendrite formation. Several studies in recent years have demonstrated the role of reduced numbers of hilar mossy cells in subsequent hippocampal excitability.26–29 Soltesz and colleagues27,28 have used large scale modeling of hippocampal excitability, in particular the dentate gyrus, to evaluate network architectural changes and their contributions to epileptogenesis and hyperexcitability. They constructed a functional model of the dentate gyrus containing several of the major glutamatergic and GABAergic cellular subtypes. Simulations using this model demonstrated that decreasing the number of hilar cells resulted in significant decreases in global connectivity, but the sprouting of granule cell axons resulted in increased local connectivity.27 The net effect of hilar cell loss and mossy fiber sprouting was increased hyperexcitability within the dentate gyrus. A recent extension of these computational studies suggested that granule cells with hilar basal dendrites could play an important role in generating seizure activity.28 Specifically, using the functional model containing hilar cell loss and mossy fiber sprouting, the inclusion of various non-random granule cell microcircuits in the dentate gyrus was explored. It was shown that a small number of highly interconnected granule cells, or “hubs”, in the network were sufficient to enhance hyperexcitability. The establishment of new synapses on basal dendrites12 is consistent with the predictions generated from this model. Even though the estimates for such hub cells range from 5 to 20% of the total granule cell population, the relatively low number of hubs was apparently large enough to promote hyperexcitability. In these computational models it is also important to note that changes in GABAergic connectivity,30–32 dentate gyrus inputs,26 cellular geometry,33 and alterations of intrinsic currents29 can also modulate granule cell and network excitability. More importantly, physiological and anatomical observations can now be modeled in silico to test new hypotheses and guide future experimental work.

Most excitatory synapses with granule cell apical dendrites are axo-spinous, and that is also true for basal dendrites.12 However, direct connections of excitatory synapses onto the dendritic shaft are up to four times more common on basal dendrites than on apical dendrites.12 Similarly, in epileptic pilocarpine-treated rats, dendrites of hilar ectopic granule cells receive a disproportionately large fraction of mossy fiber synapses directly with the dendritic shaft.19 It is unclear why these aberrant targets in the hilus are more likely to receive excitatory synapses on shafts versus spines, and the functional consequences of these excitatory shaft synapses remain to be elucidated.

The functional effects of basal dendrites are difficult to isolate and test because surgically resected tissue available for study from patients with temporal lobe epilepsy and animal models typically display mossy fiber sprouting into the molecular layer34,35 where apical dendrites are located. In these cases, aberrant recurrent excitation among granule cells could be attributable to sprouted mossy fibers that synapse with apical dendrites, basal dendrites, or both.12,36 Control, adult macaque monkeys, on the other hand, have little if any mossy fiber projections into the molecular layer - and approximately 10% of their granule cells have basal dendrites5 (as compared to control, adult rodents where they rarely occur9,37,38). In hippocampal slices from macaque monkeys, mossy fibers were antidromically stimulated and synaptic responses recorded to compare recurrent excitation in granule cells with and without basal dendrites.39 Excitatory postsynaptic currents were significantly more likely to be evoked and amplitudes were larger in granule cells with basal dendrites. However, since the stimulation paradigm might have activated other axons besides mossy fibers, the possibility of input from CA3 pyramidal cells or mossy cells to basal dendrites could not be excluded. Recordings and intracellular labeling of monosynaptically coupled pairs would be a more rigorous and direct test of the strength and efficacy of unitary synaptic events generated in basal dendrites. Even without those data, currently available functional evidence is consistent with anatomical results that show that mossy fibers synapse with basal dendrites - and thereby produce recurrent excitation among granule cells. These electrophysiological observations have also been modeled and predict virtually similar outputs - namely, enhanced excitation.28


In addition to excitatory synapses, basal dendrites in epileptic pilocarpine-treated rats receive GABAergic input (Figure 2).12 The relative proportion of GABAergic versus glutamatergic synapses is different in apical versus basal dendrites. GABAergic synapses account for 20% and 28% of all synapses with granule cell apical dendrites in control and epileptic rats, respectively.40 In contrast, GABAergic synapses account for only 7% of all synapses with hilar basal dendrites (Figure 3).12 Most GABAergic synapses are onto the dendritic shafts of basal dendrites, but there is a relatively large proportion of such synapses with spines, similar to the situation on apical dendrites.36,41 A variety of different types of GABAergic interneurons are found in the dentate gyrus, but specific sources of interneuron input to basal dendrites have not yet been identified. The presence of inhibitory synapses with granule cell basal dendrites in epileptic pilocarpine-treated rats has special significance. The presence of such synapses confirms the long suspected but indirectly supported hypothesis that GABAergic synaptogenesis occurs in mature epileptic animals.42 These observations contribute to recent, accumulating evidence that in epileptic tissue, surviving interneurons in the dentate gyrus sprout axons and form new synapses with granule cells.40,43 Although basal dendrites receive these GABAergic synapses, their numbers are relatively low compared to the sprouted excitatory synapses. The strength and efficacy of inhibitory input to basal dendrites have not yet been evaluated.

Figure 2. GABA-negative and GABA-positive axon terminals synapse (arrowheads) with the same spine of granule cell basal dendrites in epileptic rats.

Figure 2

GABA-negative and GABA-positive axon terminals synapse (arrowheads) with the same spine of granule cell basal dendrites in epileptic rats. A Electron micrograph of a spine of basal dendrite #1 labeled with electron dense reaction product. GABA-immunoreactivity (more...)

Figure 3. Summary of synapses with granule cell basal dendrites #1 and #2 from epileptic rats.

Figure 3

Summary of synapses with granule cell basal dendrites #1 and #2 from epileptic rats. Proximal is up, distal is down. Synapses are indicated by markers. Most synapses are with GABA-negative spines. “Immuno.-unk.” synapses of basal dendrite (more...)


Dashtipour et al.44 were the first to address the issue of the time course for the development of basal dendrites following seizures. Using retrograde labeling with biocytin injected into the CA3 region in hippocampal slice preparations, labeled granule cells with basal dendrites were observed seven days after pilocarpine-induced status epilepticus in rats. At the earliest time point examined in that study (3 days post-seizures), no basal dendrites were found. This study indicated that basal dendrites may form on dentate granule cells as early as one week following pilocarpine-induced seizures.44 However, the method that was used in this study required that a granule cell axon be present in the CA3 region where biocytin was injected. Thus, this method would not label newborn granule cells at this timepoint (they require about two weeks to grow their axons into CA3).45 Therefore, this study suggested that basal dendrites appeared relatively quickly after seizures (as compared to mossy fiber sprouting) but it was not determined whether these dendrites originated from newly-born granule cells.


Most granule cells with hilar basal dendrites are located at the hilar border of the granule cell layer9, and granule cell neurogenesis occurs in adults at this same location.46–48 Therefore, it seemed logical to hypothesize that the newly-generated granule cells developed hilar basal dendrites and the more mature granule cells at the molecular layer border did not display these basal dendrites. Testing the first part of this hypothesis required the use of a newborn cell marker that labels the cell body, axon and dendrites. Doublecortin was selected for this purpose because it is a protein found in dentate newborn neurons for up to 3 weeks after their birth, and is effective in labeling their growth cones, processes, and perikaryal cytoplasm.49–52 However, one confounding problem with its use was that 31% to 55% of newly born, doublecortin-labeled granule cells exhibit a basal dendrite.51,52 Such doublecortin-labeled basal dendrites are transient.37,53

To determine whether basal dendrites arise from newly born neurons, doublecortin-labeled granule cells were examined 30 days after the induction of seizures. Light microscopic preparations showed that the basal dendrites from doublecortin-labeled granule cells of epileptic rats are significantly longer than those found in the control rats.54 It was also found that 20% of newly born neurons in the epileptic rat have a basal dendrite that enters the hilus at an angle greater than 30° from its cell body. In control rats, the dendrites that emanate from the basal portion of newborn neurons are typically at an angle less than 30° from its cell body and frequently do not travel in the hilus but instead curve back into the granule cell layer (i.e., form “recurrent” basal dendrites).54 These data on doublecortin-labeled basal dendrites suggested that seizures induced morphological changes in the normally transient basal dendrite, and these changes (in length and in the angle of penetration into the hilus) may have significance for the persistence of these basal dendrites.

Another significant difference between epileptic and control animals was the presence of synapses on basal dendrites. Electron microscopy of doublecortin-labeled basal dendrites from epileptic rats showed that they had synapses.15 This observation suggested that excitatory inputs were targeting the basal dendrites of immature granule cells. In contrast, the doublecortin-labeled basal dendrites from newly-generated granule cells from animals that are not epileptic lacked synapses on their basal dendrites.15 These results were confirmed in a subsequent study where the doublecortin-labeled basal dendrites from epileptic animals were examined on each of the first five days after seizures were induced.16 No synapses were found on doublecortin-labeled basal dendrites in the first three days following pilocarpine-induced seizures.16 However, developing synapses were observed as early as 4 days after seizures on doublecortin-labeled basal dendrites.16 Therefore, synapses are found on doublecortin-labeled hilar basal dendrites at both early (4–5 days after seizures) and later (30 days after seizures) timepoints. The fact that basal dendrites are found to have synapses after seizures (see SYNAPTIC CONNECTIONS OF HILAR BASAL DENDRITES section) and they have synapses on newly-generated granule cell basal dendrites suggest that the early formed synapses may persist, perhaps by releasing trophic factors at these synapses. In addition, we hypothesized that the synaptic targeting of basal dendrites of newly-generated granule cells contributed to the persistence of hilar basal dendrites on neurons born after pilocarpine-induced seizures. Consistent with this hypothesis is the fact that no synapses are observed on doublecortin-labeled basal dendrites from control rats15 and such dendrites in non-epileptic animals are known to be transient structures.37,52,55

These data on the time course for the development of hilar basal dendrites indicate that basal dendrites may arise from seizure-induced de novo granule cells.16 A recent study by Walter et al.56 confirmed this observation and also showed that granule cells generated about a week prior to seizures may form hilar basal dendrites following seizure induction. It was suggested that those granule cells were still immature at the time seizures were induced.56,57 Together, these studies indicate that newly-generated granule cells are a major part of the population of granule cells that have hilar basal dendrites following seizures. However, it remains to be shown how the basal dendrites grow into the hilus following seizures. The following section addresses this topic.


Shapiro and Ribak58 initially hypothesized that hilar basal dendrites from newborn neurons grow along an ectopic glial scaffold. This conjecture was based on the fact the basal dendrites were found closely apposed to the horizontal processes of the radial glial-like cells that extend into the hilus (Figure 5).54 After seizures, these radial glial-like cells have a hypertrophied appearance, indicative of an inflammatory response in this region.58 In control rats, the radial glial-like cells rarely extend lengthy horizontal processes into the hilus. The same radial glial-like cells have vertical processes extending through the granule cell layer, and these vertical processes provide a scaffold for the apical dendrites of newborn neurons to grow through the granule cell layer.59,60 Thus, under normal conditions, the apical dendrite of newborn neurons grows along the radial glial-like process through the granule cell layer; following seizures, these radial glial-like cells appear hypertrophied and sprout a horizontal process that forms an ectopic glial scaffold to guide the aberrant growth of basal dendrites into the hilus. Therefore, the extension of both the radial glial-like cell’s horizontal process and the granule cell’s basal dendrite into the hilus can be thought of as a seizure-induced change.

Figure 5. Light micrographs of doublecortin-labeled newborn neurons with basal dendrites adjacent to GFAP-labeled processes from the epileptic rats.

Figure 5

Light micrographs of doublecortin-labeled newborn neurons with basal dendrites adjacent to GFAP-labeled processes from the epileptic rats. A shows a doublecortin-labeled newborn neurons (asterisk) at the border between the subgranular zone (SGZ) and the (more...)

More recently, additional support for this hypothesis was provided by Foresti et al.61 who showed that after seizures, the radial glial-like cells at the border between the granule cell layer and the subgranular zone express the chemokine receptor CCR2. Such expression is rarely seen in control animals.61 Moreover, the horizontal processes from the radial glial-like cells that orient towards the hilus also show expression of CCR2.61 Previous studies have shown that CCR2 expression on neuroblasts, together with its ligand CCL2, guides the migration of neuroblasts to sites of inflammation.62–65 These data suggest that this chemokine/receptor complex is involved in the ectopic growth and migration of immature neurons, and thus may play a role in extension of newborn granule cell basal dendrites into the hilus.

Figure 4. Schematic diagram of granule cells in the dentate gyrus of the hippocampal formation.

Figure 4

Schematic diagram of granule cells in the dentate gyrus of the hippocampal formation. A shows a normal granule cell with its dendrites in the molecular layer (ML), cell body in the granule cell layer (GL) and axon terminals (filled circles) in the hilus (more...)


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Supported by NIH/NINDS.

Copyright © 2012, Michael A Rogawski, Antonio V Delgado-Escueta, Jeffrey L Noebels, Massimo Avoli and Richard W Olsen.

All Jasper's Basic Mechanisms of the Epilepsies content, except where otherwise noted, is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported license, which permits copying, distribution and transmission of the work, provided the original work is properly cited, not used for commercial purposes, nor is altered or transformed.

Bookshelf ID: NBK98199PMID: 22787607


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