Abstract

The final common path for epileptogenesis involves pathological processes that enhance excitatory and/or decrease inhibitory synaptic transmission. In models involving traumatic- or status epilepticus–induced injury, both mechanisms underlie the epileptogenic process. Past results of the posttraumatic chronic neocortical isolation (UC) model suggested that limiting excessive excitatory connectivity with gabapentin and providing trophic support for defective GABAergic interneurons may serve as potential antiepileptogenic approaches following brain trauma. Results prompted further experiments to determine whether gabapentinoids and a small-molecule BDNF TrkB receptor partial agonist LM22A-4 (LM) would be effective in preventing seizures in posttraumatic epilepsy and genetic, noninjury epilepsy models with either enhanced excitatory synaptic connectivity (α2δ-1 overexpressing mice) or selective interneuronal abnormalities (Dravet syndrome [DS] mice with Scn1a mutation and loss of Na_v1.1 predominantly in parvalbumin [PV] interneurons). Treatment of UC rats with LM mitigated structural and functional deficits of PV interneurons and suppressed epileptiform activity. Results from α2δ-1-overexpressing mice showed that treatment with pregabalin from P7 to P28 decreased excessive excitatory synaptogenesis and seizures consisting of aberrant electroencephalogram epileptiform activity associated with behavioral arrests, for at least 90 d after the end of treatment. Treatment of DS mice with LM from P13 to P19, before onset of seizures, improved PV interneuron function and inhibitory synaptic transmission, and decreased the incidence of seizures and mortality rate. Results show that antiepileptogenic approaches in injury models where epileptogenesis is multifactorial are also effective in genetic models with limited or single epileptogenic mechanisms.

A myriad of pathological events can result in development of epilepsy (reviewed in Pitkanen and Lukasiuk, 2009; Pitkanen et al., 2009; Prince et al., 2016). The general hypothesis, supported by results from many laboratories, is that the “final common path” to epileptogenesis induced by disease processes ultimately depends on changes in relative weights of excitatory and inhibitory synaptic activities in neuronal networks. A corollary is that the end result, epileptogenesis, might be prevented by strategies that restore this delicate balance by focusing on key basic underlying synaptic mechanisms, whether the underlying etiology is traumatic, metabolic, genetic, vascular, inflammatory, or otherwise. Complexity in devising prophylactic interventions arises from the fact that the admixture of epileptogenic processes may vary depending on genetic background; maturational age; and the type, severity, and location of the inciting etiology (Prince, 2014; Prince et al., 2016). In the last volume of this series, we focused on antiepileptogenesis in chronically isolated neocortex, the “undercut” (UC) model (Prince et al., 2012), and examined effects of trauma on excitatory connectivity onto pyramidal neurons (Salin et al., 1995; Prince et al., 1997; Gu et al., 2017; Takahashi et al., 2016, 2018) and postsynaptic inhibition generated by parvalbumin (PV)-containing interneurons in the injured neocortex (Gu et al., 2017, 2018; reviewed in Prince et al., 2016). Results showed that epileptogenesis could be mitigated by postinjury treatment with GBP, which blocked excessive new excitatory connectivity (Li et al., 2012; Takahashi et al., 2018) and by activation of TrkB receptors that reversed structural and functional abnormalities in PV interneurons (Gu et al., 2018). In this chapter, we review examples of antiepileptogenesis in additional, noninjury genetic epilepsy models, in which either excessive connectivity or decreased PV interneuronal function underlies development of seizures.

Gabapentinoids, Excitatory Synapse Formation, and Antiepileptogenesis

Forming new excitatory wiring and forming synapses are normal events during early brain development that are recapitulated following neocortical and hippocampal injury (Carmichael and Chesselet, 2002; Chuckowree and Vickers, 2003; Greer et al., 2011; Jin et al., 2006; Li and Prince, 2002; Salin et al., 1995; McKinney et al., 1997; Tauck and Nadler, 1985) and in human epileptogenic temporal lobes (Davenport et al., 1990; de Lanerolle et al., 1989). High-affinity binding by astrocyte-secreted extracellular matrix proteins, thrombospondins (TSPs), to subtypes of Ca²⁺ channel subunits α2δ-1>>α2δ2, encoded by CACNA2D1 and CACNA2D2, leads to formation of excitatory synapses (Eroglu et al., 2009; Dolphin, 2012; Taylor et al., 2007) that become functional through effects of glypicans (Allen et al., 2012; Christopherson et al., 2005; Eroglu and Barres, 2010; Kucukdereli et al., 2011; Risher and Eroglu, 2012). The finding that gabapentin (GBP) binds to the TSP receptor and limits new synapse formation during development and after deafferentation injury (Eroglu et al., 2009), together with an early report that GBP has antiepileptogenic effects (Andre et al., 2003), led to experiments in a variety of models of epileptogenesis, including the partial cortical isolation (UC; Li and Prince, 2002; Takahashi et al., 2018), the freeze microgyrus (Andresen et al., 2014), stroke (Liauw et al., 2008), and post status epilepticus (Rossi et al., 2013; Perez-Ramirez et al., 2020; reviewed in D. A. Prince, pp. 370–371, in Klein et al., 2020). TSPs have other actions that may be relevant to injury-induced alterations in cortical structure such as involvement in axonal sprouting following injury (Hoffman and O’Shea, 1999; Liauw et al., 2008) and during development (Osterhout et al., 1992; reviewed in Plantman, 2013). In addition to release from astrocytes, TSPs may also be secreted by brain macrophages and stimulate neurite growth in vitro (Chamak et al., 1994).

Effects of GBP to suppress epileptogenesis in the UC model are associated with decreased neuronal death, reductions in expression of GFAP and neurofilament immunoreactivity, decreased density of excitatory synapses, and decreases in excitatory synaptic activity (Li and Prince, 2002). Use of laser scanning photo-stimulation of caged glutamate allowed mapping of the distribution of changes in excitatory connectivity following UC, changes over time, and effects of GBP treatment (Takahashi et al., 2018). There is a marked increase in the area from which excitatory inputs onto layer V Pyr neurons can be evoked (Fig. 68–1A2 vs. A1), and there are increases in response amplitude (Fig. 68–1B) that are due to increases in excitatory contacts and not to increased amplitude of individual excitatory postsynaptic currents (EPSCs). The map of increased excitatory inputs centered in layer V is remarkably similar to that obtained in earlier experiments in which axonal arbors of biocytin-filled layer V Pyr cells were mapped in the UC (cf. maps of Fig. 68–1A2 after UC with fig. 4 of Salin et al., 1995). Results show that sprouting of Pyr cell axons and excitatory synaptogenesis occurred over the 14 d after injury and that early 3 d GBP treatment had long-lasting effects to limit them (Fig. 68–1A3, B). As in earlier experiments (Li and Prince, 2002), spontaneous epileptiform bursts of EPSCs were prominent 14 d after the UC, and their frequency was decreased by early GBP treatment (Fig. 68–1C). Laser scanning photostimulation has highlighted the complexity of changes in circuit connectivity in the UC and freeze microgyrus models, where both Pyr cells and PV interneurons receive increases in excitatory and decreases in inhibitory innervation (Jin et al., 2011, 2014). The net result in both models is the emergence of epileptiform activity.

Figure 68–1.

3d GBP treatment decreased the amplitudes and narrowed the distribution of EPSCs evoked 14 days after UC. A. Composite maps of cumulative EPSCs evoked by LSPS from Pyr neurons 14 days after UC. Pia oriented up, and cell location in layer Va represented (more...)

Antiepileptogenesis in a Genetic, Noninjury Model of Epilepsy with Enhanced Excitatory Connectivity

Cortical trauma in the UC model results in a number of epileptogenic effects, including decreases in interneuronal structure and function, astrogliosis, and so on (Li and Prince, 2002) that might in some way contribute to the GBP effects in this model. Experiments in a genetic model of epileptogenesis in which excitatory synaptogenesis is increased without effects on GABAergic inhibition, the transgenic (TG) α2δ-1 overexpressing mice (Luo et al., 2001; Faria et al., 2017) have been used to further assess antiepileptogenic actions of gabapentinoids GBP and pregabalin (PGB). Excitatory cortical synapses (Vglut2/PSD95 close appositions) in this model are increased (Fig. 68–2A–C), associated with a significant increase in mEPSC frequency (Fig. 68–2D), but without alterations in spontaneous or evoked GABAergic inhibition (Faria et al., 2017). In the α2δ-1 model, the enhanced excitatory transmission is associated with epileptiform bursts in in vitro slices (Fig. 68–2E) and frequent, often prolonged seizures, consisting of behavioral arrests associated with 2–3 Hz spike waves (Fig. 68–2F). Mice also had seizures during withdrawal from light isoflurane anesthesia.

Figure 68–2.

Increased excitatory synapse density and epileptiform discharges in TG mice overexpressing α2δ-1. A and B. Representative merged confocal images of sections from control (A) and TG mice (B) reacted for Vglut2 (green) and PSD95 (red). (more...)

Further experiments in this model were done to determine whether treatment with PGB early in development would have long-term effects to limit epileptogenesis. Groups of mice were treated from P7 to P28 daily with saline or PGB50 or 100 mg/kg per day, ip (PGB50, PGB100) and video-EEG recordings obtained at intervals from P32 to P118 (4–90 d after last dose). Dual immunostaining showed a large increase in Vglut2/PSD95 colocalizations in TG cortex that was significantly reduced by 4 d PGB100 treatment (Fig. 68–3A,B). Increased mEPSC frequency in the TG cortex was significantly reduced by PGB treatment (Fig. 68–3C1,C2, D) without effects on mIPSCs. As in earlier experiments (Faria et al., 2017), EEG recordings showed frequent prolonged episodes of irregular spikes and waves during which the animal had behavioral arrests, interrupted by periods of normal baseline EEG and muscle activity (Fig. 68–3E, arrows). EEG power spectral analysis showed peaks of 2–4 Hz activity during the seizures. Analysis of EEG power at 2 Hz, beginning 4 d after the end of PGB100 treatment at P32 and extending to 90 d after last dose at P118, showed PGB effects that lasted through P118, largest at 21 and 35 d after treatment (Fig. 68–3F). These data show that PGB has prolonged significant antiepileptogenic effects in a genetic nontraumatic epilepsy model where increases in excitatory synaptogenesis and seizures occur without apparent alterations in synaptic inhibition. The mechanisms underlying such prolonged effects of gabapentinoids are unclear. GBP reduces transport of α2δ-1 calcium channels to terminals (Heblich et al., 2008) and competes with TSP binding to α2δ-1 receptors to limit new excitatory synapse formation (Eroglu et al., 2009). However, these actions are not long lasting, compared to the prolonged antiepileptogenic actions in the UC (Takahashi et al., 2018) and α2δ-1 overexpression models (Fig. 68–3). One possibility is that early prophylactic intervention limits ongoing synaptic and circuit alterations induced by epileptiform activity per se.

Figure 68–3.

PGB100 treatment decreased the density of excitatory synapses and the amplitude of epileptiform discharges in TG mice overexpressing α2δ-1. A. Representative images of co-immunostaining of Vglut2 (red) and PSD95 (green) in TG and PGB100-treated (more...)

Antiepileptogenesis in Posttraumatic Epilepsy and a Genetic Epilepsy Model with Reduced Inhibitory Interneuronal Function

Earlier results in the posttraumatic UC model of epileptogenesis showed that, in addition to other abnormalities, there were alterations in the structure and function of layer V PV interneurons and Pyr cells. Decreased immunoreactivity for BDNF on Pyr cells and for its TrkB receptor on PV interneurons was prominent (Gu et al., 2017). Given that BDNF supports growth and maintenance of GABAergic neurons during brain development (Marty et al., 1996, 1997; McAllister et al., 1999; Baldelli et al., 2002, 2005; Aguado et al., 2003), loss of trophic support from BDNF released by Pyr neurons acting on interneuronal TrkB receptors was hypothesized to be a potential mechanism underlying PV interneuronal deficits and epileptogenesis following brain trauma. Results lead to treatment of UC rats with a small-molecule TrkB partial agonist (LM22A-4 [LM; Massa et al., 2010]). LM treatment increased the density and function of PV synapses on layer V Pyr cells (Fig. 68–4A–G), enhanced inhibitory synaptic transmission, and suppressed both epileptiform activity in vitro (Fig. 68–4H, I) and PTZ evoked seizures in vivo (Gu et al., 2018). Results lead to the question of whether LM would have antiepileptogenic effects in a genetic epilepsy model, in which the principal abnormality is a defect in GABAergic interneurons. Dravet syndrome (DS) is a severe childhood epilepsy, characterized by intractable frequent seizures and comorbidities, including premature death, mainly caused by loss-of-function mutations in Scn1a gene encoding Nav1.1 that is predominantly expressed in PV interneurons (Yamakawa, 2011; Ogiwara et al., 2007). Decreased Nav1.1 impairs GABA release from PV cells, contributing to neural circuit hyperexcitability and DS phenotypes. The important role of PV cell dysfunction in the pathogenesis of DS provides a target for the development of approaches to enhance PV cell function, such as transplant of additional interneurons (Hunt et al., 2013; Zhu et al., 2018), and genetic enhancement of Scn1a expression (Colasante et al., 2020; Han et al., 2020). Results from UC model suggested that trophic activation of PV cells might be an effective therapy and led to experiments in which early treatment with LM was used to test whether it can prevent or reduce seizure activity and mortality in DS mice. Mice with the Scn1a gene mutation were treated with LM for 7 days starting at P13, before the onset of spontaneous seizures that usually begin on the third week of life. Results from immunocytochemistry, Western blot, and whole-cell patch clamp recordings showed that LM treatment (1) increased the number of perisomatic PV interneuronal synapses around cortical pyramidal cells in layer V (Fig. 68–5A–C); (2) increased Nav1.1 in PV neurons; and (3) increased inhibitory synaptic transmission (Fig. 68–5D–G). Experiments in chronically implanted DS mice showed that LM treatment decreased the incidence and frequency of spontaneous seizures and mortality rate. Results suggest that early treatment with a partial TrkB receptor agonist may be a promising therapeutic approach to enhance PV interneuron function and reduce epileptogenesis and premature death in DS.

Figure 68–4.

LM treatment increased presumptive inhibitory synapses on somata of layer V Pyr cells and suppressed epileptiform discharges in UC cortex. A and B. Biocytin-filled layer V Pyr cells (green) from saline- and LM-treated UC rats reacted with antibodies (more...)

Figure 68–5.

LM treatment increased PV synapses on somata of Pyr cells and enhanced inhibitory synaptic transmission in the cortex of DS mice. A and B. Confocal images of dual IR for PV (red) + gephyrin (green) from layer Va of sections from saline-treated (A) vs (more...)

Unresolved Issues

These results raise issues that might alter antiepileptogenic efficacy in genetic and injury-induced epilepsies. The effects of activation of TrkB in post–status epilepticus and injury models are complex (Lin et al., 2020), making it hazardous to generalize from the antiepileptogenic effects induced by TrkB activation in Dravet mice to other genetic epilepsy models or humans. Will treatment with TrkB agonists suppress epileptogenesis in genetic epilepsies where the principal defect is not in PV inhibitory interneurons, but in other types of interneurons that have different targets in cortical circuits? Previous results have shown that TrkB activation in naïve rats increases GABAergic inhibition in Pyr cells in neocortical L5 (see Fig. 7 in Gu et al., 2018), suggesting that TrkB activation will enhance inhibition even in models without GABAergic inhibitory defects. To what extent are alterations in interneuronal function, or development of increased excitatory synaptic connectivity after injury, adaptive versus maladaptive? Axonal sprouting and new connections occur as major adaptive plastic events in recovery of function after cortical lesions (Dancause et al., 2005). The age at treatment onset with TrkB activation is important because of the depolarized reversal potential for GABA_A-mediated currents in immature cortex. In diseased brain with abnormalities in Cl⁻ transport, TrkB activation might enhance seizure activity (Yuan et al., 2019; Talos et al., 2012; Watanabe et al., 2019). TrkB activation has proven to be antiepileptogenic in other models of injury-induced and genetic epilepsy (references above; Fig. 68–5; Paradiso et al., 2009; Bovolenta et al., 2010). However, antiepileptogenic versus epileptogenic effects of BDNF/TrkB activation are dependent on the underlying pathophysiology (McNamara and Scharfman, 2012), the downstream pathway activated (Lin et al., 2020), and numerous experimental variables (discussed in Gu et al., 2018; Gottmann et al., 2009). Another important variable may be the interval between injury or discovery of an epileptogenic genetic defect and treatment onset. The variability of the latent period for seizure onset after injury and failure of prophylactic trials with anticonvulsants makes it difficult to justify prolonged prophylactic treatment, in the absence of a reliable biomarker. In some genetic epilepsies where the underlying mechanism is known, treatment with an agent that affects the pathophysiological mechanism before onset of seizures may provide effective prophylaxis (Yamada et al., 2013). Our results show that early treatment with PGB in the α2δ-1 model (Fig. 68–3) has long-term effects, presumably by interfering with the epileptogenic process. The same may be true in the DS model, where TrkB activation before obvious seizure onset has prolonged effects (Fig. 68–5).

Acknowledgments

Disclosure Statement

References

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