Enhanced excitatory connectivity and decreases in GABAergic inhibition are important mechanisms underlying injury-induced epileptogenesis in many animal models and in humans. Sprouting of excitatory axons and establishment of new synapses is a ubiquitous epileptogenic response to cortical injury. In the rodent chronic partial isolation (undercut) model of posttraumatic epilepsy, tetrodotoxin treatment of undercut cortex during a critical period decreases this axonal response to injury and blocks epileptogenesis. Gabapentin, an agonist that competes with glial-derived thrombospondins at the α2δ-1 calcium subunit receptor, is antiepileptogenic in neocortical slices from undercut rats and decreases injury-induced excitatory synapse formation, cell death, and neurofilament immunoreactivity. GABAergic interneurons become atrophic and dysfunctional in undercuts, resulting in decreases in inhibitory connectivity and the strength of inhibition on pyramidal cells. A potential underlying mechanism is loss of trophic support from brain derived neurotrophic factor (BDNF) released by pyramidal neurons acting on interneuronal TrkB receptors. Treatment of undercut rats after injury with agents that mimic activation of TrkB receptors by BDNF may reduce signs of injury and dysfunction of interneurons and provide a second promising antiepileptogenic approach. A focus on limiting new excitatory connectivity and providing trophic support for injured GABAergic interneurons may allow development of effective prophylactic measures for posttraumatic epilepsy.

Spectrum of potential epileptogenic mechanisms induced by traumatic brain injury

A large number of alterations in gene expression¹⁹ and a variety of pathophysiological processes occur in parallel following a brain injury^20–22, reviewed in^7,23, making it unlikely that an intervention focused on any one of these, in isolation, will emerge as a prophylactic “silver bullet”. The situation is further complicated by the likelihood that variables such as the level of brain maturation, site and distribution of injury (focal vs. multifocal vs. diffuse), type of trauma (e.g. concussive versus penetrating), presence or absence of significant bleeding, and other factors may affect the underlying type and sequence of epileptogenic events and the optimal timing of a potentially successful intervention in a given individual. Do different combinations of pathophysiological mechanisms underlie human epileptogenesis that follows different types of cortical injuries such as those due to stroke with cortical infarction, penetrating vs. closed concussive head injuries, focal infections or other etiologies? The same question is relevant to potential similarities or differences in events underlying chronic epileptogenesis in various models of TBI such as fluid percussion injury²⁴ versus controlled cortical impact²⁵ versus neocortical partial isolation or “undercut”²⁶. Are underlying mechanisms in these models in neocortex the same as those in posttraumatic temporal lobe epilepsy models, or when hippocampal damage is induced by status epilepticus rather than direct trauma? These are critical questions because they bear on potential prophylactic therapies and, unfortunately, the detailed data required for answers are incomplete.

A survey of the limited cellular results from neocortical injury models, and from animals whose temporal lobes are injured in the course of experimental status epilepticus, as well as from available human material, indicates that two pathophysiological processes are prominent in focal epileptogenesis, namely, enhanced excitatory connectivity^10,27–34, and alterations in GABAergic inhibitory mechanisms^33,35–40. But even within these broad categories, different types of abnormalities may be present that will require different prophylactic or therapeutic approaches. For example, disinhibition might involve alterations in gamma-aminobutyric acid A (GABA_A) receptor subunits^41,42, decreases in voltage dependent calcium channels⁴⁰ or Na+/K+ adenosine triphosphatase (ATPase) at inhibitory terminals^43,44, shifts in the chloride gradient due to changes in expression of chloride transporters KCC2 or NKCC^45–47, loss of inhibitory connectivity due to structural changes in interneurons^16,48 or actual loss of interneurons of various subtypes^36,38.

Subsets of abnormalities can also affect the mechanisms controlling excitation, such as alterations in the probability of release (Pr) at terminals⁴⁹, burst firing in axons⁵⁰, reviewed in⁵¹, receptor efficacy or number^52–56, and dysfunction of ion or transmitter transport^57–62. In addition to alterations in inhibitory efficacy and enhanced excitation, many other potentially epileptogenic changes are present following injury such as alterations in voltage dependent ion channels^63–67, blood brain barrier disturbances⁶⁸, inflammatory responses and release of cytokines^21,69, alterations in glia^70,71, and so on. In terms of evaluation of therapeutic trials of potential prophylactic agents, this plethora of abnormalities raises a difficult issue: a single agent may fail to prevent PTE, even though it is effective at its intended target, that is a false negative result may be obtained due to the presence of other epileptogenic mechanisms acting in parallel.

Choice of models for research on posttraumatic epilepsy

There is no perfect model of human posttraumatic epilepsy. The advantages and disadvantages of acute and chronic models of epilepsy have recently been reviewed in detail⁷². Fluid percussion injury, controlled cortical impact and undercut models each have their place in advancing our understanding of PTE. Valuable information has also been obtained from status epilepticus temporal lobe injury models, although direct traumatic injury is not present and the resulting epileptogenesis represents a different epilepsy syndrome that may involve a somewhat different spectrum of underlying mechanisms. Discussions about the merits of one model versus another thus are only useful in the context of the particular pathophysiological process or event to be investigated. Obviously, to determine whether a drug will be prophylactic against seizures in vivo, a model in which there might be extensive injury and an expected high incidence of electrographic and behavioral posttraumatic seizures at relatively short latency after injury (i.e. high throughput), would be most practical and desirable.^73–75 However, this might not be the model of choice for investigation of the details of functional or structural alterations in neocortical GABAergic interneurons or pyramidal cells that occur at a site of stereotyped restricted epileptogenic focal injury, and the potential prophylactic effects induced by the same drug on these alterations. Such a question would be better addressed with a more reductionistic approach using a model that would facilitate detailed cellular in vitro experiments and avoid the complications of widespread damage and variability.^30,32,76 Both kinds of experiments are critical for progress, and fitting the preparation used to the question posed is certainly not a new concept in neurobiological research. There is no one best approach to unraveling the mechanisms underlying the pathogenesis and prophylaxis of PTE.

Partial neocortical isolation (“undercut”) model

The authors’ familiarity with this model, the significant amount of anatomical and cellular electrophysiological data available (references below and in⁷⁷) and the fact that this is the first case in which prophylaxis of epileptogenesis after local cortical injury has been demonstrated (discussion below), has lead us to focus on the undercut model in this review. The advantages of this model have been detailed elsewhere.⁷⁷ Most important is the relatively short interval between injury and epileptiform activity that is present in a high proportion of neocortical slices cut through the damaged area and maintained in vitro ^78–80 (Figure 1C,D). This has allowed the detailed examination of epileptogenic cellular structural and functional alterations in pyramidal (Pyr) cells and GABAergic interneurons detailed below. We have also obtained in vivo video/electroencephalographic (EEG) recordings that show electrographic and behavioral seizures beginning with focal discharge in the undercut cortex, spreading across the cortex on the injured side and propagating contralaterally (Figure 2 in⁷⁷).

Figure 1

Undercut cortex in rats and humans. A: Coronal section of human brain in patient who underwent undercutting surgery of right frontal lobe for intractable pain. Dashed white lines drawn through the undercut here and in C. (Modified from Scoville WB. Selective (more...)

Figure 2

Structural alterations in fast-spiking interneurons in undercut cortex. A,B: Images of single layer V fast-spiking interneurons filled with biocytin and processed in control (A) and undercut slice (B). The cell from the undercut has thinner dendrites (more...)

Partially isolated neocortical islands with intact pial circulation (“undercuts” below) are an established in vivo and in vitro model for development of chronic post-traumatic hyperexcitability and epileptogenesis^{32,78,79,81,82}, and partially isolated neocortex is also epileptogenic in man⁸³; Figure 1A). The undercut cortex retains normal laminations (Figure 1B), although it becomes thinner with modest cell loss and obvious structural alterations in deep lying pyramidal (Pyr) cells^78,84, (K Graber and DA Prince, unpublished). Disinhibition, increases in neuronal membrane excitability, and increases in excitatory synaptic coupling have been suggested as potential mechanisms in this chronic epilepsy model.^{32,78,85–87} The undercut cortex becomes progressively more epileptogenic over several weeks^82,88, and spontaneous interictal discharges can persist for at least 1 year in the monkey²⁶. The time of onset of epileptogenesis, or the “critical period” in rats occurs during the first 3 days after injury⁸⁹ and recent data suggest that epileptogenic activity is already present at 3 days after the undercut (DK Takahashi and DA Prince, unpublished results). Isolated islands of neocortical gray matter, with neuropathological evidence of substantial axonal reorganization, are also present in postmortem specimens from epileptic children who developed extensive underlying white matter lesions as infants⁹⁰. Interictal epileptiform activity can be recorded within partially isolated cortex of anesthetized rats, and c-fos immunoreactivity (IR) is increased for weeks in the injured cortex, suggesting ongoing abnormal activity⁹¹. Behavioral and electrographic seizures occur in in vivo experiments on monkey, cat and rodents in this model (see above and references in⁷⁷). Areas of partially isolated cortex with underlying loss of white matter are also present in the cortical contusion (Figure 2 in²⁵ and fluid percussion injury models (Figure 1D in²³), although it is not clear whether seizure activity originates from the cortex above these sites. Of interest are reports of chronic electrographic and clinical seizures in humans as a complication of psychosurgery in which connections from portions of frontal lobes were severed, essentially producing large partially isolated neocortical slabs ^92,93 (Figure 1A).

Abnormalities in GABAergic inhibitory mechanisms in undercut cortex

A variety of structural and electrophysiological evidence shows that GABAergic inhibition is compromised in undercut cortex. Recent experiments in the cat suggest that glutamic acid decarboxylase (GAD-) or GABA- positive neocortical interneurons are selectively and progressively reduced in density in cat undercut cortex⁸⁴. Although our initial cell counts in undercut rat cortex have not shown a selective decrease in density of parvalbumin (PV)-immunoreactive interneurons¹²⁰, we have found significant structural changes in biocytin-filled fast-spiking PV-containing cells, including marked decreases in axonal lengths and dendritic volume (Figure 2), giving them an appearance similar to that seen in immature PV interneurons (cf Figure 3A of¹²¹ with Figure 2B). Further, the axons of these interneurons in the undercut cortex have a significant increase in the proportion of small (<1 um in diameter) boutons and a decrease in numbers of larger (>1 um in diameter) boutons (see Figure 5 in¹⁶), changes that would be associated with altered pre- and postsynaptic structures at GABAergic synapses and with less effective inhibitory transmission^122,123.

Figure 3

Loss of perisomatic α3Na+K+ ATPase in undercut cortex. A: Immumoreactivity (IR) for α3Na+K+ATPase in layer V of control cortex contralateral and homotopic to undercut on rat 21d after lesion. IR is localized around the somata of pyramidal (more...)

Figure 5

Gabapentin (GBP) in vivo reduces epileptogenesis and excitatory synapse density in undercut slices. A–B: Field potentials evoked in layer V of undercut slice by stimuli in partial cortical isolations 14 d after injury. A: Rat was treated with (more...)

Results of several electrophysiological experiments confirm a decreased efficacy of GABAergic inhibitory transmission in the undercut cortex. Whole cell recordings in rat undercut slices showed a decreased frequency of mIPSCs in Pyr cells³³, and quantitative electronmicroscopic experiments confirmed a decreased density of symmetrical (inhibitory) synapses on somata of layer V Pyr cells (J. Wenzel, PA Schwartzkroin and DA Prince, unpublished results) as one potential mechanism for decreased miniature inhibitory postsynaptic current (mIPSC) frequency. More recently, we have also shown that the axonal terminals of layer V interneurons in undercuts are abnormal in that they have a decreased probability of GABA release and increased failure rate⁴⁰ due in part to a downregulation of N-type calcium channels in terminals.^123a Dual recordings from synaptically coupled FS-Pyr or FS-spiny stellate pairs in layer IV of undercuts showed a decrease in Pr, a large reduction in the amplitude of unitary IPSCs, increased coefficient of variation and increased failures, indicating alterations in presynaptic terminals of the largest subgroup of GABAergic neurons in cortex, FS cells ^123b. Neuronal injury can also decrease the efficacy of postsynaptic inhibition by decreasing expression of KCC2 and impairing outward chloride transport^124,125. In the undercut, there are also decreases in KCC2 and in the outward transport of chloride in postsynaptic Pyr cells that would make GABAergic inhibition less effective at times of high frequency activity¹²⁶. Recent results, obtained with laser scanning photostimulation of caged glutamate in combination with whole cell recordings, have shown that the net effects of some of the above-mentioned anatomical and electrophysiological abnormalities are to reduce the spatial extent of inhibitory inputs onto both Pyr cells and FS interneurons in the chronic undercut¹²⁷.

Fast-spiking interneurons in neocortex normally have a high density of Na⁺-K⁺ ATPase (“sodium pump”) in their membranes⁴⁴ and particularly in their axonal terminals surrounding Pyr cell somata^43,128; (Figure 3A). Sodium pump activation would be important in fast-firing neurons to prevent excessive increases in [Na⁺]_i that might depolarize terminals and decrease GABA release. There is a significant loss of Na pump immunoreactivity in undercut cortex surrounding Pyr cells (Figure 3B), similar to that previously found in the freeze-microgyrus model of epileptogenesis⁴³, suggesting another potential mechanism that would lead to terminal dysfunction and decreased GABA release.

When does posttraumatic epileptogenesis begin?

Answers to this critical question would influence decisions about the timing of potential antiepileptogenic treatment. From the available data, it appears likely that processes eventually leading to hyperexcitability in cortical networks and to seizures may be set into motion at the time of the TBI, although the latency to the first behavioral spontaneous seizure is highly variable. Seizures in the first week after injury are usually not followed by epilepsy in man; however they are associated with an increased statistical risk of subsequent epilepsy³, indicating that, at least in some individuals, an epileptogenic process is initiated early. Epileptiform activity may be initially undetectable by surface EEG, making this an unreliable marker of the onset of epileptogenesis¹²⁹. There is evidence for early emergence of epileptogenesis in a variety of experimental data. In models of acute neocortical trauma, epileptiform activity may develop within minutes or hours after injury in vitro^130,131 and results from acute partial isolation experiments done under ketamine anesthesia in cats do show that acute epileptiform discharges are generated in cortex near the isolation¹³². However the underlying mechanisms in these early seizures may be different from those in more chronic models in that they might involve acute alterations such as release of excitatory amino acids¹³¹, spreading depression, large increases in [K⁺]_o and blood-brain barrier disruption.

Recently we recorded in vitro from undercut slices obtained 3 days after the injury and found that they generate robust prolonged spontaneous and evoked epileptiform field potentials associated with large amplitude EPSCs. Confocal images obtained after immunocytochemical processing for GAP43, vesicular glutamate transporter 1 (vGLUT1) and postsynaptic density (PSD)95 have suggested that there is significant sprouting of excitatory axons onto pyramidal somata within days after the undercut is placed. Other electrophysiological data suggest that these sprouted terminals are functional and contribute to epileptogenesis (D.K. Takahashi and D.A. Prince, unpublished).

Axonal sprouting and excitatory synapse formation occur in parallel with a number of other pathophysiological events following TBI (e.g. alterations in GABAergic inhibition discussed above, intrinsic changes in membrane excitability⁷⁸), so it is difficult to determine whether hyperconnectivity alone would be sufficient to induce posttraumatic epileptogenesis. A potential answer to this question comes from recent results in C1q knockout mice that have behavioral and electrographic seizures resulting from failure to prune excitatory cortical synapses during development.¹³³ In vitro slices from these animals are epileptogenic due to increased excitatory connectivity without apparent alterations in inhibitory events.

In experiments using controlled cortical impact (CCI), epileptiform activity and electrographic seizures are present in vitro at the first week after injury¹⁰ and appear to progress with generation of “ictal” discharges lasting for many seconds by the second week. In other experiments such as those involving kainate kindling, epileptogenic activity is present early in hippocampus but goes undetected in in vivo recordings from the usual skull electrodes¹³⁴. Our previous results in the undercut model provided the first proof-in principle that posttraumatic epileptogenesis, as gauged by the occurrence of epileptiform activity in in vitro slices, begins shortly after injury and can be prevented⁸⁰. However this prophylaxis was only effective if the treatment, namely topical exposure of the injured cortex to tetrodotoxin (TTX) in a slow release resin, was administered for the first 3 days after injury. Later applications were ineffective at limiting the proportion of slices that were epileptogenic⁸⁹. Thus the results revealed a brief critical period of a few days beginning after the partial isolation when the seeds for subsequent epileptogenesis are sown in the undercut cortex model. Tetrodotoxin has also been effective in decreasing axonal sprouting and rhythmic neocortical burst discharges that begin by the second day after thermocoagulation lesions in rat neocortex, although the relationship to later epileptogenesis is unclear.¹¹⁰ These results with TTX appear contrary to the hypothesis that the enhanced excitability and epileptogenesis in the undercut may be due to activation of homeostatic increases in excitatory neurotransmission due to deafferentation^118,135. It is possible that homeostatic compensatory increases in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors do occur, but are offset by decreases in innervation of postsynaptic targets induced by the TTX treatment. Immunocytochemical analysis of undercut cortex shows that TTX blockade of activity down-regulates anatomical markers of the axonal and terminal sprouting response that are evident as early as 3 days after injury (Figure 4A–C) and are long-lasting (Figure 4D–F). Other as yet unexplored results of silencing injured cortex may account for the blockade of hyperexcitability in the undercut that outlasts the TTX treatment by many months (K.D. Graber and D.A. Prince, unpublished results). It is important to note that TTX may produce quite different (opposite) effects on epileptogenesis when given during early development in hippocampus¹³⁶, a result that emphasizes the difficulty of generalizing results from one model to another in terms of potential prophylactic approaches.

Figure 4

Immunoreactivity (IR) of axons and terminals in partially isolated neocortex. A–C: Sections through layer V of rat sensorimotor cortex reacted with growth-associated protein (GAP) 43 antibody. D–F: Comparable sections from rats reacted (more...)

Prophylaxis of posttraumatic epileptogenesis

Potential approaches to modification of the increased excitatory sprouting and synapse formation and decreased GABAergic interneuronal structure/function, are suggested by results of experiments dealing with normal development of excitatory synapses and interneurons.

Important unresolved issues affecting application of antiepileptogenic therapies for PTE

1. The question of adaptive vs. maladaptive changes in connectivity following injury is a key one that must be considered in approaching potential preventative treatments that decrease epileptogenic sprouting. A number of reports implicate axonal sprouting and new connections as major adaptive plastic events in recovery of function after cortical lesions^108,109. In recent experiments in a stroke model where middle cerebral artery occlusion induces expression of TSPs in astrocytes, TSP1–2 knock-out mice showed significant defects in the axonal sprouting and synaptic density compared to wild type animals, together with defects in functional recovery¹⁴⁰. The post-stroke incidence of epilepsy was not studied in these experiments; however the results, and those in the above references, provide a cautionary note.
2. A number of pathophysiological processes occur in parallel after a serious epileptogenic brain injury. Although any one of these in isolation might not induce seizure activity, in combination their effects on excitability would summate and epileptogenesis could result. Thus, a single prophylactic approach might be ineffective and a “prophylactic cocktail” might be required.
3. Two key elements in developing epileptogenesis in a variety of injury models are reductions in functional GABAergic inhibition and enhanced new excitatory connectivity. Although attempts to reverse such alterations may be effective, the relationships between both excitatory and inhibitory circuit function, circuit repair and epileptiform activity are complex. GABAergic synchronization of cortical networks occurs in epileptogenic cortical lesions¹⁵², and in both acute¹⁵³ and genetic models of epileptiform discharge¹⁵⁴. Also, depolarizing GABA responses due to altered chloride gradients occur in excitatory cells during development¹⁵⁵ and after injury^125,156. These factors make the net effect of enhanced interneuronal output hard to predict. Antiepileptogenesis, through decreases in excitatory circuit activities might also have obverse effects such as decreased activation of interneurons¹⁵⁷; but see^158–160 or reduced activity-dependent axonal sprouting, pathfinding and circuit repair^110,161,162.
4. As more becomes known about processes controlling excitation and inhibition during cortical development or following injury, it is possible that prophylactic therapies selectively affecting maladaptive processes might be applied. One important obstacle at this time is the unavailability of a reliable biological marker that would select for individuals who will go on to develop post-traumatic epilepsy, although it is clear that the incidence increases with the severity of brain injury (reviewed in¹⁶³).
5. We know little about the temporal extent of critical periods in man when prophylactic intervention would be effective, or how to identify epileptogenesis “in progress”. The latent period may be very long between injury and expression of behavioral seizures¹; however the critical period for intervention could closely follow injury^89,164.
6. Finally, multiple offsetting potential effects of a given intervention are possible, such as both enhancement of excitatory connectivity together with “rescue” of inhibitory interneurons by TrkB receptor agonists (e.g. ^165,166).

The chapters in this volume suggest that significant progress is being made in understanding the basic mechanisms leading to epilepsy, and that we may have potential prophylactic therapies available in the years to come, providing that some of the issues mentioned above are settled by detailed basic and clinical investigations.

Acknowledgements

Supported by NIH grants NS12151, NS39579 and NS06477 from the NINDS and a grant from Citizens United for Research in Epilepsy.

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