Frequency-dependent seizure-suppressing effects of optogenetic activation of septal inhibitory cells in mesial temporal lobe epilepsy.

Mesial temporal lobe epilepsy (MTLE) is characterized by recurring focal seizures that arise from limbic areas and are often refractory to pharmacological interventions. We have reported that optogenetic stimulation of PV-positive cells in the medial septum at 0.5 Hz exerts seizure-suppressive effects. Therefore, we compared here these results with those obtained by optogenetic stimulation of medial septum PV-positive neurons at 8 Hz in male PV-ChR2 mice (P60-P100) undergoing an initial, pilocarpine-induced status epilepticus (SE). Optogenetic stimulation (5 min ON, 10 min OFF) was performed from day 8 to day 12 after SE at a frequency of 8 Hz (n = 6 animals) or 0.5 Hz (n = 8 animals). Surprisingly, in both groups, no effects were observed on the occurrence of interictal spikes and interictal high frequency oscillations (HFOs). However, 0.5 Hz stimulation induced a significant decrease of seizure occurrence (p < 0.05). Such anti-ictogenic effect was not observed in the 8 Hz protocol that instead triggered seizures (p < 0.05); these seizures were significantly longer under optogenetic stimulation compared to when optogenetic stimulation was not implemented (p < 0.05). Analysis of ictal HFOs revealed that in the 0.5 Hz group, but not in the 8 Hz group, seizures occurring under optogenetic stimulation were associated with significantly lower rates of fast ripples compared to when optogenetic stimulation was not performed (p < 0.05). Our results indicate that activation of GABAergic PV-positive neurons in the medial septum exerts seizure-suppressing effects that are frequency-dependent and associated with low rates of fast ripples. Optogenetic activation of medial septum PV-positive neurons at 0.5 Hz is efficient in blocking seizures in the pilocarpine model of MTLE, an effect that did not occur with 8 Hz stimulation.

Ictal activity is sustained by the estrogen receptor ß during the estrous cycle.

Catamenial epilepsy, defined as a periodicity of seizure exacerbation during the menstrual cycle, affects up to 70 % of epileptic women. Seizures in these patients are often non-responsive to medication; however, our understanding of the relation between menstrual cycle and seizure generation (i.e. ictogenesis) remains limited. We employed here field potential recordings in the in vitro 4-aminopyridine model of epileptiform synchronization in female mice (P60-P130) and found that: (i) the estrous phase favors ictal activity in the entorhinal cortex; (ii) these ictal discharges display an onset pattern characterised by the presence of chirps that are thought to mirror synchronous interneuron firing; and (iii) blocking estrogen receptor ß-mediated signaling reduces ictal discharge duration. Our findings indicate that the duration of 4AP-induced ictal discharges, in vitro, increases during the estrous phase, which corresponds to the human peri-ovulatory period. We propose that these effects are caused by the presumptive enhancement of interneuron excitability due to increased estrogen receptor ß-mediated signaling.

GABAB receptor outward currents are transiently disclosed by the convulsant 4-aminopyridine in vitro.

The K+ channel blocker 4-aminopyridine (4AP) has been extensively used to investigate the mechanisms underlying neuronal network synchronization in both in vitro and in vivo animal models of focal epilepsy. 4AP-induced effects are paralleled by an increase in both excitatory and inhibitory neurotransmitter release, but the mechanisms of action of 4AP on neuronal networks remain unclear. By employing simultaneous whole-cell patch clamp and field potential recordings from hippocampal CA3/4 pyramidal layer of acute brain slices obtained from mice (n = 30), we found that the appearance of epileptiform discharges induced by 4AP (100 µM) is consistently preceded by the transient recurrence of presumptive GABAB outward currents, which are not mirrored by any field activity. These GABAB outward currents still occurred during application of ionotropic glutamatergic antagonists (n = 12 cells) but were blocked by the GABAB receptor antagonist CGP55845 (n = 7). Our findings show that the transient occurrence of distinct GABAB outward currents precedes the appearance of 4AP-induced neuronal network synchronization leading to epileptiform activity in the rodent hippocampus in vitro.

CA3 principal cell activation triggers hypersynchronous-onset seizures in a mouse model of mesial temporal lobe epilepsy.

Mesial temporal lobe epilepsy (MTLE) is the most common form of focal epilepsy and it is characterized by seizures that are often refractory to medications. Seizures in MTLE have two main patterns of onset that have been termed hypersynchronous (HYP) and low-voltage fast (LVF) and are believed to mainly depend on the activity of excitatory principal cells and inhibitory interneurons, respectively. In this study, we investigated whether unilateral open-loop optogenetic activation of CaMKII-positive principal cells in the hippocampus CA3 region favors the generation of spontaneous HYP seizures in kainic acid-treated (KA) CaMKII-ChR2 mice. Optogenetic activation of CA3 principal cells (1 Hz, 180 s ON, 220 s OFF) was implemented for 15 days after KA-induced status epilepticus. We found that both LVF and HYP seizures occurred in nonstimulated CaMKII-ChR2 (n = 6) and stimulated CaMKII-Cre (n = 5) mice. In contrast, optogenetic activation of principal cells in CaMKII-ChR2 mice (n = 5) triggered only HYP seizures that were characterized by high fast ripple (250-500 Hz) rates during the pre-ictal and ictal periods. These results provide firm evidence that in MTLE spontaneous seizures with different onset patterns depend on distinct neuronal network mechanisms of generation. They also demonstrate that HYP seizures occurring in vivo along with their associated fast ripples depend on the activity of principal cells in the CA3 region.NEW & NOTEWORTHY Previous evidence suggested that different seizure onset patterns rely on the activity of distinct neuronal populations. In this study, we show for the first time that in vivo optogenetic stimulation of CaMKII principal cells in kainic acid-treated mice triggers hypersynchronous-onset seizures that are associated with fast ripples. Our findings indicate that in patients with predominant HYP-onset seizures, anticonvulsant treatments should be aimed at limiting the firing of principal neurons in the seizure onset zone.

Can in vitro studies aid in the development and use of antiseizure therapies? A report of the ILAE/AES Joint Translational Task Force.

In vitro preparations (defined here as cultured cells, brain slices, and isolated whole brains) offer a variety of approaches to modeling various aspects of seizures and epilepsy. Such models are particularly amenable to the application of anti-seizure compounds, and consequently are a valuable tool to screen the mechanisms of epileptiform activity, mode of action of known anti-seizure medications (ASMs), and the potential efficacy of putative new anti-seizure compounds. Despite these applications, all disease models are a simplification of reality and are therefore subject to limitations. In this review, we summarize the main types of in vitro models that can be used in epilepsy research, describing key methodologies as well as notable advantages and disadvantages of each. We argue that a well-designed battery of in vitro models can form an effective and potentially high-throughput screening platform to predict the clinical usefulness of ASMs, and that in vitro models are particularly useful for interrogating mechanisms of ASMs. To conclude, we offer several key recommendations that maximize the potential value of in vitro models in ASM screening. This includes the use of multiple in vitro tests that can complement each other, carefully combined with in vivo studies, the use of tissues from chronically epileptic (rather than naïve wild-type) animals, and the integration of human cell/tissue-derived preparations.

Specific quinone reductase 2 inhibitors reduce metabolic burden and reverse Alzheimer's disease phenotype in mice.

Biological aging can be described as accumulative, prolonged metabolic stress and is the major risk factor for cognitive decline and Alzheimer's disease (AD). Recently, we identified and described a quinone reductase 2 (QR2) pathway in the brain, in which QR2 acts as a removable memory constraint and metabolic buffer within neurons. QR2 becomes overexpressed with age, and it is possibly a novel contributing factor to age-related metabolic stress and cognitive deficit. We found that, in human cells, genetic removal of QR2 produced a shift in the proteome opposing that found in AD brains while simultaneously reducing oxidative stress. We therefore created highly specific QR2 inhibitors (QR2is) to enable evaluation of chronic QR2 inhibition as a means to reduce biological age-related metabolic stress and cognitive decline. QR2is replicated results obtained by genetic removal of QR2, while local QR2i microinjection improved hippocampal and cortical-dependent learning in rats and mice. Continuous consumption of QR2is in drinking water improved cognition and reduced pathology in the brains of AD-model mice (5xFAD), with a noticeable between-sex effect on treatment duration. These results demonstrate the importance of QR2 activity and pathway function in the healthy and neurodegenerative brain and what we believe to be the great therapeutic potential of QR2is as first-in-class drugs.

Excitatory neuron-specific suppression of the integrated stress response contributes to autism-related phenotypes in fragile X syndrome.

Dysregulation of protein synthesis is one of the key mechanisms underlying autism spectrum disorder (ASD). However, the role of a major pathway controlling protein synthesis, the integrated stress response (ISR), in ASD remains poorly understood. Here, we demonstrate that the main arm of the ISR, eIF2α phosphorylation (p-eIF2α), is suppressed in excitatory, but not inhibitory, neurons in a mouse model of fragile X syndrome (FXS; Fmr1-/y). We further show that the decrease in p-eIF2α is mediated via activation of mTORC1. Genetic reduction of p-eIF2α only in excitatory neurons is sufficient to increase general protein synthesis and cause autism-like behavior. In Fmr1-/y mice, restoration of p-eIF2α solely in excitatory neurons reverses elevated protein synthesis and rescues autism-related phenotypes. Thus, we reveal a previously unknown causal relationship between excitatory neuron-specific translational control via the ISR pathway, general protein synthesis, and core phenotypes reminiscent of autism in a mouse model of FXS.

Optogenetic activation of septal inhibitory cells abates focal seizures.

Emerging evidence suggests that the medial septum can control seizures occurring in focal epileptic disorders, thus representing a therapeutic target. Therefore, we investigated whether continuous optogenetic activation of inhibitory parvalbumin (PV)-positive interneurons in the medial septum can reduce the occurrence of spontaneous seizures in the pilocarpine model of mesial temporal lobe epilepsy (MTLE). Light pulses (450 nm, 25 mW, 20-ms pulse duration) were delivered at 0.5 Hz (5 min ON, 10 min OFF) with a laser diode fiber light source between day 8 and day 12 after status epilepticus (SE) in PV-ChR2 mice (n = 8). Seizure rates were significantly lower during time periods of optogenetic stimulation (days 8-12) compared with before implementation of optogenetics (days 4-7) (P < 0.05). Moreover, between day 13 and day 21 after SE seizure rates were still significantly lower compared with before optogenetic stimulation (i.e., between day 4 and day 7) (P < 0.05). No seizures were recorded between day 10 and day 12 in all animals, and no seizures occurred up to 3 days after the end of optogenetic stimulation (days 13-15). Our findings indicate that activation of PV interneurons in the medial septum abates seizures in the pilocarpine model of MTLE. Moreover, the persisting anti-ictogenic effects suggest that stimulation of the medial septum could alter the progression of MTLE.NEW & NOTEWORTHY The medial septum could represent a therapeutic target to treat patients with focal epilepsy. In this study, we show that optogenetic activation of inhibitory parvalbumin-positive interneurons in the medial septum can block spontaneous seizures and prevents their reoccurrence for ∼5 days after the end of stimulation. Our findings suggest that the anti-ictogenic effects induced by stimulation of the medial septum could also alter the progression of mesial temporal lobe epilepsy.

Evolution of interictal activity in models of mesial temporal lobe epilepsy.

Interictal activity and seizures are the hallmarks of focal epileptic disorders (which include mesial temporal lobe epilepsy, MTLE) in humans and in animal models. Interictal activity, which is recorded with cortical and intracerebral EEG recordings, comprises spikes, sharp waves and high-frequency oscillations, and has been used in clinical practice to identify the epileptic zone. However, its relation with seizures remains debated. Moreover, it is unclear whether specific EEG changes in interictal activity occur during the time preceding the appearance of spontaneous seizures. This period, which is termed "latent", has been studied in rodent models of MTLE in which spontaneous seizures start to occur following an initial insult (most often a status epilepticus induced by convulsive drugs such as kainic acid or pilocarpine) and may mirror epileptogenesis, i.e., the process leading the brain to develop an enduring predisposition to seizure generation. Here, we will address this topic by reviewing experimental studies performed in MTLE models. Specifically, we will review data highlighting the dynamic changes in interictal spiking activity and high-frequency oscillations occurring during the latent period, and how optogenetic stimulation of specific cell populations can modulate them in the pilocarpine model. These findings indicate that interictal activity: (i) is heterogeneous in its EEG patterns and thus, presumably, in its underlying neuronal mechanisms; and (ii) can pinpoint to the epileptogenic processes occurring in focal epileptic disorders in animal models and, perhaps, in epileptic patients.

Ligand-gated mechanisms leading to ictogenesis in focal epileptic disorders.

We review here the neuronal mechanisms that cause seizures in focal epileptic disorders and, specifically, those involving limbic structures that are known to be implicated in human mesial temporal lobe epilepsy. In both epileptic patients and animal models, the initiation of focal seizures - which are most often characterized by a low-voltage fast onset EEG pattern - is presumably dependent on the synchronous firing of GABA-releasing interneurons that, by activating post-synaptic GABAA receptors, cause large increases in extracellular [K+] through the activation of the co-transporter KCC2. A similar mechanism may contribute to seizure maintenance; accordingly, inhibiting KCC2 activity transforms seizure activity into a continuous pattern of short-lasting epileptiform discharges. It has also been found that interactions between different areas of the limbic system modulate seizure occurrence by controlling extracellular [K+] homeostasis. In line with this view, low-frequency electrical or optogenetic activation of limbic networks restrain seizure generation, an effect that may also involve the activation of GABAB receptors and activity-dependent changes in epileptiform synchronization. Overall, these findings highlight the paradoxical role of GABAA signaling in both focal seizure generation and maintenance, emphasize the efficacy of low-frequency activation in abating seizures, and provide experimental evidence explaining the poor efficacy of antiepileptic drugs designed to augment GABAergic function in controlling seizures in focal epileptic disorders.

Involvement of GABAergic Interneuron Subtypes in 4-Aminopyridine-Induced Seizure-Like Events in Mouse Entorhinal Cortex in Vitro.

Single-unit recordings performed in temporal lobe epilepsy patients and in models of temporal lobe seizures have shown that interneurons are active at focal seizure onset. We performed simultaneous patch-clamp and field potential recordings in entorhinal cortex slices of GAD65 and GAD67 C57BL/6J male mice that express green fluorescent protein in GABAergic neurons to analyze the activity of specific interneuron (IN) subpopulations during acute seizure-like events (SLEs) induced by 4-aminopyridine (4-AP; 100 µm). IN subtypes were identified as parvalbuminergic (INPV, n = 17), cholecystokinergic (INCCK), n = 13], and somatostatinergic (INSOM, n = 15), according to neurophysiological features and single-cell digital PCR. INPV and INCCK discharged at the start of 4-AP-induced SLEs characterized by either low-voltage fast or hyper-synchronous onset pattern. In both SLE onset types, INSOM fired earliest before SLEs, followed by INPV and INCCK discharges. Pyramidal neurons became active with variable delays after SLE onset. Depolarizing block was observed in ∼50% of cells in each INs subgroup, and it was longer in IN (∼4 s) than in pyramidal neurons (<1 s). As SLE evolved, all IN subtypes generated action potential bursts synchronous with the field potential events leading to SLE termination. High-frequency firing throughout the SLE occurred in one-third of INPV and INSOM We conclude that entorhinal cortex INs are very active at the onset and during the progression of SLEs induced by 4-AP. These results support earlier in vivo and in vivo evidence and suggest that INs have a preferential role in focal seizure initiation and development.SIGNIFICANCE STATEMENT Focal seizures are believed to result from enhanced excitation. Nevertheless, we and others demonstrated that cortical GABAergic networks may initiate focal seizures. Here, we analyzed for the first time the role of different IN subtypes in seizures generated by 4-aminopyridine in the mouse entorhinal cortex slices. We found that in this in vitro focal seizure model, all IN types contribute to seizure initiation and that INs precede firing of principal cells. This evidence is in agreement with the active role of GABAergic networks in seizure generation.

GABAA signaling, focal epileptiform synchronization and epileptogenesis.

Under physiological conditions, neuronal network synchronization leads to different oscillatory EEG patterns that are associated with specific behavioral and cognitive functions. Excessive synchronization can, however, lead to focal or generalized epileptiform activities. It is indeed well established that in both epileptic patients and animal models, focal epileptiform EEG patterns are characterized by interictal and ictal (seizure) discharges. Over the last three decades, employing in vitro and in vivo recording techniques, several experimental studies have firmly identified a paradoxical role of GABAA signaling in generating interictal discharges, and in initiating-and perhaps sustaining-focal seizures. Here, we will review these experiments and we will extend our appraisal to evidence suggesting that GABAA signaling may also contribute to epileptogenesis, i.e., the development of plastic changes in brain excitability that leads to the chronic epileptic condition. Overall, we anticipate that this information should provide the rationale for developing new specific pharmacological treatments for patients presenting with focal epileptic disorders such as mesial temporal lobe epilepsy (MTLE).

Modulation of in vitro epileptiform activity by optogenetic stimulation of parvalbumin-positive interneurons.

GABAA signaling is surprisingly involved in the initiation of epileptiform activity since increased interneuron firing, presumably leading to excessive GABA release, often precedes ictal discharges. Field potential theta (4-12 Hz) oscillations, which are thought to mirror the synchronization of interneuron networks, also lead to ictogenesis. However, the exact role of parvalbumin-positive (PV) interneurons in generating theta oscillations linked to epileptiform discharges remains unexplored. We analyzed here the field responses recorded in the CA3, entorhinal cortex (EC), and dentate gyrus (DG) during 8-Hz optogenetic stimulation of PV-positive interneurons in brain slices obtained from PV-ChR2 mice during 4-aminopyridine (4AP) application. This optogenetic protocol triggered similar field oscillations in both control conditions and during 4AP application. However, in the presence of 4AP, optogenetic stimuli also induced: 1) interictal discharges that were associated in all regions with 8-Hz field oscillations and 2) low-voltage fast onset ictal discharges. Interictal and ictal events occurred more frequently during optogenetic activation than during periods of no stimulation. 4AP also increased synchronicity during PV-interneuron activation in all three regions. In opsin-negative mice, optogenetic stimulation did not change the rate of both types of epileptiform activity. Our findings suggest that PV-interneuron recruitment at theta (8 Hz) frequency contributes to epileptiform synchronization in limbic structures in the in vitro 4AP model.NEW & NOTEWORTHY Previous studies have identified contradictory roles of PV-interneurons in ictogenesis and the link between theta oscillations and epileptiform activity remains unexplored. Here, we investigated in vitro the effect of PV-interneuron optogenetic stimulation under 4AP in temporal lobe regions obtained from PV-ChR2 transgenic mice. Under theta (8 Hz) optogenetic stimulation and 4AP application, interictal spikes and low-voltage fast onset ictal discharges were triggered, suggesting that the activation of PV-interneurons favors synchronization and ictogenesis.

Bilateral optogenetic activation of inhibitory cells favors ictogenesis.

Mesial temporal lobe epilepsy (MTLE) is the most common type of focal refractory epilepsy and is characterized by recurring seizures that are often refractory to medication. Since parvalbumin-positive (PV) interneurons were recently shown to play significant roles in ictogenesis, we established here how bilateral optogenetic stimulation of these interneurons in the hippocampus CA3 regions modulates seizures, interictal spikes and high-frequency oscillations (HFOs; ripples: 80-200 Hz, fast ripples: 250-500 Hz) in the pilocarpine model of MTLE. Bilateral optogenetic stimulation of CA3 PV-positive interneurons at 8 Hz (lasting 30 s, every 2 min) was implemented in PV-ChR2 mice for 8 consecutive days starting on day 7 (n = 8) or on day 13 (n = 6) after pilocarpine-induced status epilepticus (SE). Seizure occurrence was higher in both day 7 and day 13 groups of PV-ChR2 mice during periods of optogenetic stimulation ("ON"), compared to when stimulation was not performed ("OFF") (day 7 group = p < 0.01, day 13 group = p < 0.01). In the PV-ChR2 day 13 group, rates of seizures (p < 0.05), of interictal spikes associated with fast ripples (p < 0.01), and of isolated fast ripples (p < 0.01) during optogenetic stimulations were significantly higher than in the PV-ChR2 day 7 group. Our findings reveal that bilateral activation of PV-interneurons in the hippocampus (leading to a presumptive increase in GABA signaling) favors ictogenesis. These effects may also mirror the neuropathological changes that occur over time after SE in this animal model.

GABAB Receptors: are they Missing in Action in Focal Epilepsy Research?

GABA, the key inhibitory neurotransmitter in the adult forebrain, activates pre- and postsynaptic receptors that have been categorized as GABAA, which directly open ligand-gated (or receptor-operated) ion-channels, and GABAB, which are metabotropic since they operate through second messengers. Over the last three decades, several studies have addressed the role of GABAB receptors in the pathophysiology of generalized and focal epileptic disorders. Here, we will address their involvement in focal epileptic disorders by mainly reviewing in vitro studies that have shown: (i) how either enhancing or decreasing GABAB receptor function can favour epileptiform synchronization and thus ictogenesis, although with different features; (ii) the surprising ability of GABAB receptor antagonism to disclose ictal-like activity when the excitatory ionotropic transmission is abolished; and (iii) their contribution to controlling seizure-like discharges during repetitive electrical stimuli delivered in limbic structures. In spite of this evidence, the role of GABAB receptor function in focal epileptic disorders has been attracting less interest when compared to the numerous studies that have addressed GABAA receptor signaling. Therefore, the main aim of our mini-review is to revive interest in the function of GABAB receptors in focal epilepsy research.

Kresimir Krnjevic (1927-2021) and GABAergic inhibition: a lifetime dedication.

After over seven decades of neuroscience research, it is now well established that γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. In this paper dedicated to Kresimir Krnjevic (1927-2021), a pioneer and leader in neuroscience, we briefly highlight the fundamental contributions he made in identifying GABA as an inhibitory neurotransmitter in the brain and our personal interactions with him. Of note, between 1972 and 1978 Dr. Krnjevic was a highly reputed Chief Editor of the Canadian Journal of Physiology and Pharmacology.

Sensory processing dysregulations as reliable translational biomarkers in SYNGAP1 haploinsufficiency.

Amongst the numerous genes associated with intellectual disability, SYNGAP1 stands out for its frequency and penetrance of loss-of-function variants found in patients, as well as the wide range of co-morbid disorders associated with its mutation. Most studies exploring the pathophysiological alterations caused by Syngap1 haploinsufficiency in mouse models have focused on cognitive problems and epilepsy; however, whether and to what extent sensory perception and processing are altered by Syngap1 haploinsufficiency is less clear. By performing EEG recordings in awake mice, we identified specific alterations in multiple aspects of auditory and visual processing, including increased baseline gamma oscillation power, increased theta/gamma phase amplitude coupling following stimulus presentation and abnormal neural entrainment in response to different sensory modality-specific frequencies. We also report lack of habituation to repetitive auditory stimuli and abnormal deviant sound detection. Interestingly, we found that most of these alterations are present in human patients as well, thus making them strong candidates as translational biomarkers of sensory-processing alterations associated with SYNGAP1/Syngap1 haploinsufficiency.

The pilocarpine model of mesial temporal lobe epilepsy: Over one decade later, with more rodent species and new investigative approaches.

Fundamental work on the mechanisms leading to focal epileptic discharges in mesial temporal lobe epilepsy (MTLE) often rests on the use of rodent models in which an initial status epilepticus (SE) is induced by kainic acid or pilocarpine. In 2008 we reviewed how, following systemic injection of pilocarpine, the main subsequent events are the initial SE, the latent period, and the chronic epileptic state. Up to a decade ago, rats were most often employed and they were frequently analysed only behaviorally. However, the use of transgenic mice has revealed novel information regarding this animal model. Here, we review recent findings showing the existence of specific neuronal events during both latent and chronic states, and how optogenetic activation of specific cell populations modulate spontaneous seizures. We also address neuronal damage induced by pilocarpine treatment, the role of neuroinflammation, and the influence of circadian and estrous cycles. Updating these findings leads us to propose that the rodent pilocarpine model continues to represent a valuable tool for identifying the basic pathophysiology of MTLE.

4E-BP2-dependent translation in parvalbumin neurons controls epileptic seizure threshold.

The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) integrates multiple signals to regulate critical cellular processes such as mRNA translation, lipid biogenesis, and autophagy. Germline and somatic mutations in mTOR and genes upstream of mTORC1, such as PTEN, TSC1/2, AKT3, PIK3CA, and components of GATOR1 and KICSTOR complexes, are associated with various epileptic disorders. Increased mTORC1 activity is linked to the pathophysiology of epilepsy in both humans and animal models, and mTORC1 inhibition suppresses epileptogenesis in humans with tuberous sclerosis and animal models with elevated mTORC1 activity. However, the role of mTORC1-dependent translation and the neuronal cell types mediating the effect of enhanced mTORC1 activity in seizures remain unknown. The eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and 2 (4E-BP2) are translational repressors downstream of mTORC1. Here we show that the ablation of 4E-BP2, but not 4E-BP1, in mice increases the sensitivity to pentylenetetrazole (PTZ)- and kainic acid (KA)-induced seizures. We demonstrate that the deletion of 4E-BP2 in inhibitory, but not excitatory neurons, causes an increase in the susceptibility to PTZ-induced seizures. Moreover, mice lacking 4E-BP2 in parvalbumin, but not somatostatin or VIP inhibitory neurons exhibit a lowered threshold for seizure induction and reduced number of parvalbumin neurons. A mouse model harboring a human PIK3CA mutation that enhances the activity of the PI3K-AKT pathway (Pik3caH1047R-Pvalb ) selectively in parvalbumin neurons shows susceptibility to PTZ-induced seizures. Our data identify 4E-BP2 as a regulator of epileptogenesis and highlight the central role of increased mTORC1-dependent translation in parvalbumin neurons in the pathophysiology of epilepsy.