Epileptogenic Effects Research Articles

The risk of unprovoked seizure occurrence after status epilepticus in adults.

Status epilepticus (SE) may lead to long-term consequences. This study evaluated the risk and predictors of seizure occurrence after SE, with a focus on SE due to acute symptomatic etiologies. Prospectively collected data about adults surviving a first non-hypoxic SE were reviewed. The outcome was the occurrence of unprovoked seizures during the follow-up. Kaplan-Meier survival curve analysis and log-rank test were used to analyze the time to seizure occurrence and determine the statistical significance between etiological groups. Three subcategories within acute etiology were considered according to the presence of the following: (1) structural lesion (acute-primary); (2) brain involvement during systemic disorders (acute-secondary); and (3) drug or alcohol intoxication/withdrawal (acute-toxic). Cox proportional hazards model was adopted to estimate hazard ratios (HRs) with the 95% confidence intervals (CIs). Two hundreds fifty-seven individuals were included. Fifty-four subjects (21.0%) developed seizures after a median of 9.9 (interquartile range 4.3-21.7) months after SE. The estimated 1-, 2-, and 5-year rates of seizure occurrence according to acute SE etiologies were 19.4%, 23.4%, and 30.1%, respectively, for acute-primary central nervous system (CNS) pathology; 2.2%, 2.2%, and 8.7%, respectively, for acute-secondary CNS pathology; and 0%, 9.1%, and 9.1%, respectively, for acute-toxic causes. Five-year rates of seizure occurrence for non-acute SE causes were 33.9% for remote, 65.7% for progressive, and 25.9% for unknown etiologies. In multivariate Cox regression model, progressive etiology (adjusted HR [adjHR] 2.27, 95% CI 1.12-4.58), SE with prominent motor phenomena evolving in non-convulsive SE (adjHR 3.17, 95% CI 1.38-7.25), and non-convulsive SE (adjHR 2.38, 95% CI 1.16-4.90) were independently associated with higher hazards of unprovoked seizures. Older people (adjHR .98, 95% CI .96-.99) and people with SE due to acute-secondary CNS pathology (adjHR .18, 95% CI .04-.82) were at decreased risk of seizure occurrence. SE carries a risk of subsequent seizures. Both the underlying cause and epileptogenic effects of SE are likely to contribute.

The Role of Epileptic Activity in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia. Epileptic seizures or epileptic activity have been detected in AD, and people with epilepsy have a higher risk of dementia compared to the general population. This suggests that seizures or epileptic activity might often coexist with AD. It is increasingly evident that epileptic activity or seizures are common but often overlooked comorbidities of AD. However, the causal relationship between seizures, epileptic activity and cognitive decline remains uncertain. Experimental data show that amyloid-β (Aβ) and Tau protein can cause neuronal hyperexcitability and has epileptogenic effects. Neural network hyperexcitation regulates the ratio of Aβ isoforms and is linked to the initiation of AD, indicating a shared mechanism. Clinical studies suggest that cognitive impairment accelerates in AD patients with seizures or epileptic activity. This review discusses the relationship between epileptic seizures and AD, the impact of epileptic activity in AD, and potential treatments.

Tramadol use and seizure: A case report

Opioids are commonly used and abused substance worldwide. Tramadol hydrochloride is a synthetic, centrally acting, opiate-like analgesic. Seizure is a rare side effect of tramadol. Tramadol-related seizures are short, tonic-clonic seizures that, like other drug-related seizures, are self-limiting. This epileptogenic effect of tramadol occurs at both low and high doses. We, herein, report the development of seizures after the use of tramadol with increasing dose. We report a 19-year-old man who had opioid dependence syndrome with regular use resulting into multiple episodes of seizures diagnosed as epilepsy for which Sodium valproate had been started.

Unexpected epileptogenic effect of lethal doses of pentobarbital: a case report

Background: Barbiturate poisoning is rare but potentially fatal. Case Report: We reported a case of barbiturate poisoning in a 28-year-old woman who recovered from lethal pentobarbital deliberate self-poisoning. The initial blood pentobarbital concentration was 61 mg/L, corresponding to a potentially lethal dose. Despite the ingestion of a high dose of pentobarbital, the electroencephalogram revealed an unattended pattern compatible with possible nonconvulsive status epilepticus. Following resuscitation maneuvers, appropriate care, and antiseizure medication, the patient awakened after 7 days. The evolution was excellent without neurological deficits at 2 months.Conclusion: Despite the expected and known effects of high-dose pentobarbital in reducing and suppressing cortical activity in the brain, the present case demonstrates that lethal dose of pentobarbital may have an epileptogenic effect. Our hypothesis was that the mechanism of the origin of such a picture is a relatively abrupt decrease in toxic doses of pentobarbital, resulting in a withdrawal phenomenon.

A team science approach for the preclinical and clinical characterization and biomarker development for post‐traumatic epilepsy

AbstractObjectivePost‐traumatic epilepsy (PTE) is an acquired epilepsy that develops in the months or years following a traumatic brain injury (TBI) and can lead to substantial personal, financial, and societal burden. To date, PTE is rarely curable; current treatments are partially effective and often accompanied by adverse side effects. While research on PTE has expanded significantly in the last several years, there remain numerous challenges to identifying effective prevention and treatment strategies. In this paper, we describe advances from the CURE Epilepsy PTE Initiative, including its implementation and the emphasis on team science.MethodsThe CURE Epilepsy PTE Initiative funded six research teams to link preclinical and clinical studies to engage in the validation of experimental models, characterization of pathophysiology and biological pathways, and identification of risk factors associated with PTE. Three teams had projects with both a preclinical and a clinical component; these teams focused on: targeting the epileptogenic effects of subarachnoid blood, exploring the neuropathological mechanisms of epileptogenesis, and defining the role of extracellular matrix injury. Two teams undertook entirely preclinical projects: exploring the role of vascular injury, gliosis, and neurogenesis as drivers for PTE, and identifying genetic, proteomic, metabolomic, and microRNA biosignatures to improve the prediction of PTE. One team's project was entirely clinical and investigated genetic and protein biomarkers to improve the prediction of PTE.ResultsIn addition to scientific discoveries including characterization of a variety of animal models and progress towards the understanding of biological underpinnings and biomarkers for PTE, significant programmatic and personnel‐related processes were incorporated, including standardized, rigorous policies and procedures to ensure quality and accountability between and within groups.SignificanceWe propose CURE Epilepsy's team science approach as an effective way to bring together a diverse set of investigators to explore biological mechanisms that may lead to cures for the epilepsies.

Epilepsy diagnosis after Covid-19: A population-wide study

BackgroundWe aimed to investigate whether SARS-CoV-2 infection was associated with an increased risk of incident epilepsy. MethodsNational register-based matched study. Verified cases of SARS-CoV-2 infection were acquired from the system for communicable disease surveillance in Sweden (SmiNet) and linked to data from the National Patient Register (NPR) and Cause of Death register in Sweden. Cases and non-infected controls were compared using a Cox proportional hazards model. ResultsA total of 1,221,801 SARS-CoV-2 infected patients and 1,223,312 controls were included. Infection was not associated with an increased risk of epilepsy on a whole population level (HR 1.01, 95% CI 0.92–1.12). Statistically significant effects were observed in patients between 61 and 80 years (HR 1.66, 95% CI 1.37–2.02), also when adjusting for stroke, traumatic brain injury, tumours (same age group HR 1.50, 95% CI 1.24–1.82) and mechanical ventilation (HR 1.28, 95% CI 1.05–1.57). In patients 81–100 years, a similar significant difference was observed (HR 1.77, 95% CI 1.30–2.42), which remained after adjustment for stroke, traumatic brain injury and tumours (HR 1.51, 95% CI 1.10–2.05) but not when mechanical ventilation was included as a covariate (HR 1.34, 95% CI 0.97–1.84). ConclusionsOn a whole population level, SARS-CoV-2 infections is not associated with an increased risk of epilepsy. In patients above 60 years, a moderately increased risk of epilepsy was observed. However, considering potential non-controllable bias and that Covid-19 patients in intensive care present with a lower risk than the general ICU population, the virus-induced epileptogenic effect is likely very small.

Relation between orexin A and epileptic seizures

IntroductionOne of the unknown mechanisms in epilepsy pathogenesis is the involvement of the hypothalamic neuropeptide orexin. Although the relationship between orexin and sleep has been revealed, its effect in epilepsy has not been fully clarified. In this study, we aimed to show the relationship between orexin A and the seizures that occur during sleep and wakefulness. Material and methodsThis study included 40 patients with drug-resistant focal epilepsy and 37 healthy controls. Night basal orexin (NBO) and morning basal orexin (MBO) levels were measured using enzyme-linked immunosorbent assay in patients and controls. Serum samples were collected from patients after epileptic seizures during sleep and wakefulness. ResultsIn both patients and controls, MBO levels (median: 1039 pg/mL, interquartile ranges [IQR] (899–1078)) were higher than NBO levels (median 989 pq/mL, IQR (893–1078) (p = 0.02). Basal orexin levels were lower in patients than in controls (p < 0.001). However, while the duration of seizures was shortened in awake seizures, the level of orexin increased (p = 0.007). Additionally, orexin levels after nocturnal seizure were higher in patients who had an ictal electroencephalography onset in the left hemisphere or a lesion in the left temporal lobe (p = 0.02; p = 0.01, respectively). There was no relationship between postictal somnolence and orexin levels. Although there was no significant difference, the level of post-seizure orexin increased compared to the basal values, especially in seizures during sleep. DiscussionThe increase in serum orexin levels, especially after seizures, suggests that orexin may be associated with the epileptogenic effect. In further studies, determination of orexin from cerebrospinal fluid (CSF) and correlation of CSF and serum orexin levels may provide more useful information regarding the relationship between orexin and epilepsy.

A Comparison of Epileptogenic Effect of Status Epilepticus Treated With Diazepam, Midazolam, and Pentobarbital in the Mouse Pilocarpine Model of Epilepsy

Status epilepticus (SE) is a medical emergency associated with acute severe systemic damage and high mortality. Moreover, symptomatic SE is one of the highest risk factors for epileptogenesis. While the antiepileptic drugs (AEDs) are chosen in favor of acute control of SE, the potential short-term and long-term effects of such AEDs have been ignored in clinics. In this study, we hypothesized that AEDs that are used to control acute SE might affect the feasibility for the chronic development of epileptogenesis after SE. Therefore, we sought to compare the epileptogenic effects of SE that are terminated by three AEDs, i.e., diazepam, midazolam, and pentobarbital, which are widely used as first-line anti-SE AEDs. For this purpose, we used a mouse model of SE induced by intraperitoneal (i.p.) injection of lithium chloride (LiCl)-pilocarpine. The pilocarpine-induced SE was terminated with diazepam, midazolam, or pentobarbital. Then we compared short-term and long-term effects of SE with different AED treatments by examining SE-associated mortality and behavioral spontaneous recurrent seizures (SRSs) and by using magnetic resonance imaging (MRI) and immunohistochemistry to evaluate pathological and cellular alterations of mice in the different treatment groups. We found that i.p. injections of diazepam (5 mg/kg), midazolam (10 mg/kg), and pentobarbital (37.5 mg/kg) were able to terminate acute pilocarpine-SE effectively, while pentobarbital treatment showed less neuroprotective action against lethality in the short phase following SE. Long-term evaluation following SE revealed that SE treated with midazolam had resulted in relatively less behavioral SRS, less hippocampal atrophy, and milder neuronal loss and gliosis. Our data revealed an obvious advantage of midazolam vs. diazepam or pentobarbital in protecting the brain from epileptogenesis. Therefore, if midazolam provides as strong action to quench SE as other AEDs in clinics, midazolam should be the first choice of anti-SE AEDs as it provides additional benefits against epileptogenesis.

The usage of clozapine in a patient with schizophrenia and epilepsy: A case report

IntroductionThe usage of clozapine in patients with schizophrenia and epilepsy raises many challenges due to the epileptogenic effects of the drug. There is little data about using clozapine for treatment of treatment-resistant schizophrenia (TRS) accompanied by epilepsy.ObjectivesTo present a case report illustrating a patient diagnosed with epilepsy and TRS, successfully treated with clozapine.MethodsA literature review on “PubMed” database was conducted, using the keywords: clozapine, antipsychotics, epilepsy, seizures, psychoses. Information regarding the clinical case was obtained by consulting the patient’s file.ResultsWe present a woman, 33 years old with mild intellectual disability and a 10-year history of schizophrenia. At the age of 24, the patient lost consciousness and experienced tonic – clonic seizure, but epilepsy was not diagnosed. The patient was hospitalized multiple times due to positive symptoms of schizophrenia and suicidal thoughts. Various combinations of neuroleptics and electroconvulsive therapy were used for treatment without therapeutic effect. At the age of 32, a diagnosis of TRS was established, leading to treatment with a moderate clozapine dose (400mg/day). At the fifth month of treatment with clozapine un episode of generalized seizures occurred, leading to a diagnosis of idiopathic generalized epilepsy. Since then, the patient was treated with levetiracetam and the dosage of clozapine was lowered to 275mg/d. The seizures did not re-occur and clinical response to the psychiatric treatment was positive.ConclusionsThis case report highlights how clozapine can be used safely and effectively for patients with TRS and epilepsy and how the epileptogenic effects can be moderated by using antiepileptics in the overall treatment scheme.DisclosureNo significant relationships.

Deletion of the Na-K-2Cl cotransporter NKCC1 results in a more severe epileptic phenotype in the intrahippocampal kainate mouse model of temporal lobe epilepsy

Increased neuronal expression of the Na-K-2Cl cotransporter NKCC1 has been implicated in the generation of seizures and epilepsy. However, conclusions from studies on the NKCC1-specific inhibitor, bumetanide, are equivocal, which is a consequence of the multiple potential cellular targets and poor brain penetration of this drug. Here, we used Nkcc1 knockout (KO) and wildtype (WT) littermate control mice to study the ictogenic and epileptogenic effects of intrahippocampal injection of kainate. Kainate (0.23 μg in 50 nl) induced limbic status epilepticus (SE) in both KO and WT mice with similar incidence, latency to SE onset, and SE duration, but the number of intermittent generalized convulsive seizures during SE was significantly higher in Nkcc1 KO mice, indicating increased SE severity. Following SE, spontaneous recurrent seizures (SRS) were recorded by continuous (24/7) video/EEG monitoring at 0-1, 4-5, and 12-13 weeks after kainate, using depth electrodes in the ipsilateral hippocampus. Latency to onset of electrographic SRS and the incidence of electrographic SRS were similar in WT and KO mice. However, the frequency of electrographic seizures was lower whereas the frequency of electroclinical seizures was higher in Nkcc1 KO mice, indicating a facilitated progression from electrographic to electroclinical seizures during chronic epilepsy, and a more severe epileptic phenotype, in the absence of NKCC1. The present findings suggest that NKCC1 is dispensable for the induction, progression and manifestation of epilepsy, and they do not support the widely held notion that inhibition of NKCC1 in the brain is a useful strategy for preventing or modifying epilepsy.

Reduced GABAergic Neuron Excitability, Altered Synaptic Connectivity, and Seizures in a KCNT1 Gain-of-Function Mouse Model of Childhood Epilepsy

SUMMARYGain-of-function (GOF) variants in K+ channels cause severe childhood epilepsies, but there are no mechanisms to explain how increased K+ currents lead to network hyperexcitability. Here, we introduce a human Na+-activated K+ (KNa) channel variant (KCNT1-Y796H) into mice and, using a multiplatform approach, find motor cortex hyperexcitability and early-onset seizures, phenotypes strikingly similar to those of human patients. Although the variant increases KNa currents in cortical excitatory and inhibitory neurons, there is an increase in the KNa current across subthreshold voltages only in inhibitory neurons, particularly in those with non-fast-spiking properties, resulting in inhibitory-neuron-specific impairments in excitability and action potential (AP) generation. We further observe evidence of synaptic rewiring, including increases in homotypic synaptic connectivity, accompanied by network hyperexcitability and hypersynchronicity. These findings support inhibitory-neuron-specific mechanisms in mediating the epileptogenic effects of KCNT1 channel GOF, offering cell-type-specific currents and effects as promising targets for therapeutic intervention.

The effect of fampridine on the risk of seizure in patients with multiple sclerosis

BackgroundFampridine was first approved by the US Food and Drug Administration (FDA) to improve walking in multiple sclerosis (MS) patients, which was demonstrated by an increase in their walking speed. Nevertheless, the medication has been reported to possess an epileptogenic effect since it blocks the voltage-gated potassium channels in neural fibers. Several studies have indicated that the risk of seizure among fampridine consumers is not substantially higher than that in the general MS population, however. The objective of this study is to describe 97 MS patients for whom fampridine was prescribed and to assess the incidence of post-medication seizures. MethodsThis cohort study included 97 MS patients with gait problems who referred to the Isfahan Clinic of MS from August 2017 to September 2019. The exclusion criteria were a previous or family history of seizure or a history of renal impairment. Fampridine was prescribed for all the patients at a dose of 10 mg twice daily (12 hours apart). Resultsthree patients (with an approximate incidence rate of 0.015 per 100 patient-years) presented with generalized tonic-clonic seizures, 7, 9, and 14 months after initiating fampridine consumption. The radiological findings revealed significant cortical and subcortical lesions in the three patients. Further, two of them consumed baclofen or fingolimod simultaneously with fampridine. ConclusionThe reported incidence rate is relatively higher than that in the general MS population. The extensive (sub) cortical lesions and the concomitant medications probably have an important role in the epileptogenesis, regardless of fampridine. However, the potential pro-convulsant properties of fampridine should not be overlooked.

Effects of immunization with heat-killed Mycobacterium vaccae on autism spectrum disorder-like behavior and epileptogenesis in a rat model of comorbid autism and epilepsy

Autism spectrum disorders (ASDs) and epilepsy are often comorbid. The basis for this co-occurrence remains unknown; however, inflammatory stressors during development are a shared risk factor. To explore this association, we tested the effect of repeated immunizations using a heat-killed preparation of the stress-protective immunoregulatory microbe Mycobacterium vaccae NCTC 11,659 (M. vaccae) on the behavioral and epileptogenic consequences of the combined stress-terbutaline (ST) rat model of ASD-like behavior/epilepsy. Repeated immunization of the dam with M. vaccae during pregnancy, followed by immunization of the pups after terbutaline injections, prevented the expression of ASD-like behavior but did not appear to protect against, and may have even enhanced, the spontaneous epileptogenic effects of ST. Maternal M. vaccae injections transferred an anti-inflammatory immunophenotype to offspring, and repeated injections across development prevented ST-induced increases in microglial density at early developmental time points in a region-specific manner. Despite epidemiological comorbidity between ASD/epileptic conditions and shared environmental risk factors, our results suggest that the expression of ASD-like behaviors, but perhaps not epileptogenesis, is sensitive to early anti-inflammatory intervention. These data provide support for the exploration of immunoregulatory strategies to prevent the negative neurodevelopmental behavioral effects of stressors during early critical periods.

E-I E-I Woe: Mossy Cell Regulation of Granule Cell Activity in Temporal Lobe Epilepsy.

An Excitatory and Epileptogenic Effect of Dentate Gyrus Mossy Cells in a Mouse Model of Epilepsy Botterill JJ, Lu YL, LaFrancois JJ, Bernstein HL, Alcantara-Gonzalez D, Jain S, Leary P, Scharfman HE. Cell Rep. 2019;29(9):2875-2889.e6. doi:10.1016/j.celrep.2019.10.100.The sparse activity of hippocampal dentate gyrus (DG) granule cells (GCs) is thought to be critical for cognition and behavior, whereas excessive DG activity may contribute to disorders such as temporal lobe epilepsy. Glutamatergic mossy cells (MCs) of the DG are potentially critical to normal and pathological functions of the DG because they can regulate GC activity through innervation of GCs or indirectly through GABAergic neurons. Here, we test the hypothesis that MC excitation of GCs is normally weak, but under pathological conditions, MC excitation of GCs is dramatically strengthened. We show that selectively inhibiting MCs during severe seizures reduced manifestations of those seizures, hippocampal injury, and chronic epilepsy. In contrast, selectively activating MCs was proconvulsant. Mechanistic in vitro studies using optogenetics further demonstrated the unanticipated ability of MC axons to excite GCs under pathological conditions. These results demonstrate an excitatory and epileptogenic effect of MCs in the DG.

Tocilizumab in pediatric refractory status epilepticus and acute epilepsy: Experience in two patients

There is growing evidence for inflammation as a cause and/or consequence of seizures in epilepsy as certain inflammatory biomarkers are elevated. Interleukin (IL)-6, with pro-inflammatory and epileptogenic effects, can perpetuate seizures. Clinical and experimental data support its involvement in acute refractory situations, with some cases responding to treatment with tocilizumab, a humanized monoclonal antibody against the IL-6 receptor. We describe 2 pediatric cases of refractory epilepsy with an abrupt debut responding to tocilizumab. Advances in the knowledge of inflammatory biomarkers involved in epilepsy and the targeted treatment could have important benefits, especially in cases that are refractory to usual treatments.

An Excitatory and Epileptogenic Effect of Dentate Gyrus Mossy Cells in a Mouse Model of Epilepsy

SUMMARYThe sparse activity of hippocampal dentate gyrus (DG) granule cells (GCs) is thought to be critical for cognition and behavior, whereas excessive DG activity may contribute to disorders such as temporal lobe epilepsy (TLE). Glutamatergic mossy cells (MCs) of the DG are potentially critical to normal and pathological functions of the DG because they can regulate GC activity through innervation of GCs or indirectly through GABAergic neurons. Here, we test the hypothesis that MC excitation of GCs is normally weak, but under pathological conditions, MC excitation of GCs is dramatically strengthened. We show that selectively inhibiting MCs during severe seizures reduced manifestations of those seizures, hippocampal injury, and chronic epilepsy. In contrast, selectively activating MCs was pro-convulsant. Mechanistic in vitro studies using optogenetics further demonstrated the unanticipated ability of MC axons to excite GCs under pathological conditions. These results demonstrate an excitatory and epileptogenic effect of MCs in the DG.

The Paroxysmal Depolarization Shift: Reconsidering Its Role in Epilepsy, Epileptogenesis and Beyond.

Paroxysmal depolarization shifts (PDS) have been described by epileptologists for the first time several decades ago, but controversy still exists to date regarding their role in epilepsy. In addition to the initial view of a lack of such a role, seemingly opposing hypotheses on epileptogenic and anti-ictogenic effects of PDS have emerged. Hence, PDS may provide novel targets for epilepsy therapy. Evidence for the roles of PDS has often been obtained from investigations of the multi-unit correlate of PDS, an electrographic spike termed “interictal” because of its occurrence during seizure-free periods of epilepsy patients. Meanwhile, interictal spikes have been found to be associated with neuronal diseases other than epilepsy, e.g., Alzheimer’s disease, which may indicate a broader implication of PDS in neuropathologies. In this article, we give an introduction to PDS and review evidence that links PDS to pro- as well as anti-epileptic mechanisms, and to other types of neuronal dysfunction. The perturbation of neuronal membrane voltage and of intracellular Ca2+ that comes with PDS offers many conceivable pathomechanisms of neuronal dysfunction. Out of these, the operation of L-type voltage-gated calcium channels, which play a major role in coupling excitation to long-lasting neuronal changes, is addressed in detail.

CASE REPORT ON SEIZURE WITH CO ADMINISTRATION OF LEVOFLOXACIN AND THEOPHYLINE

Case Summary: An 84-year-old man was admitted to the hospital due to seizure episodes. One week before the patient was admitted to the same hospital with complaints of COPD exacerbation and was discharged with a prescription of levofloxacin, theophylline ceftriaxone, pantaprazole, montelukast, methylprednisolone, budesonide nebulization, ipratropium bromide nebulization, and syrup codylex. After receiving one dose of oral levofloxacin, the patient experienced a seizure. The patient was hyperglycaemic at the time of admission and had no history of a seizure disorder. Discussion: Here the cause of seizure could be a drug-drug interaction (between theophylline and levofloxacin) with CYP1A2 substrates with no epileptogenic effects which could augment the concentration of levofloxacin and consequently results in seizures. In spite of that, it has to be kept in mind that the drug-drug interactions originate at various pharmacodynamic and pharmacokinetic levels and that drugs CYP affinities are rarely completely CYP-specific. Thus levofloxacin may have drug interactions at the level of CYPs other than CYP1A2. Conclusion: the clinicians are advised to closely monitor the possibility of seizures in COPD patients who+ are taking both levofloxacin and theophylline. The physicians should also be encouraged to use the techniques of TDM to individualize the dose of narrow therapeutic drugs to avoid serious adverse effects.

A Novel Excitatory and Epileptogenic Effect of Dentate Gyrus Mossy Cells in a Mouse Model of Epilepsy

The sparse activity of hippocampal dentate gyrus (DG) granule cells (GCs) is thought to be critical for cognition and behavior, whereas excessive DG activity is thought to contribute to disorders such as temporal lobe epilepsy (TLE). Glutamatergic mossy cells (MCs) of the DG are potentially critical to normal and pathological functions of the DG because they can regulate GC activity through direct innervation of GCs or indirectly through GABAergic neurons. Here we test the hypothesis that MC excitation of GCs is normally weak, but under special conditions, MC excitation of GCs is robust. Our results show that selectively inhibiting MCs during severe seizures reduced the severity of those seizures, hippocampal injury, and chronic epilepsy. Mechanistic in vitro studies using optogenetics further demonstrated the underappreciated ability of MC axons to robustly excite GCs under specific conditions. These results demonstrate a conditional excitatory effect of MCs in the DG

Soman-induced status epilepticus, epileptogenesis, and neuropathology in carboxylesterase knockout mice treated with midazolam.

SummaryObjectiveExposure to chemical warfare nerve agents (CWNAs), such as soman (GD), can induce status epilepticus (SE) that becomes refractory to benzodiazepines when treatment is delayed, leading to increased risk of epileptogenesis, severe neuropathology, and long‐term behavioral and cognitive deficits. Rodent models, widely used to evaluate novel medical countermeasures (MCMs) against CWNA exposure, normally express plasma carboxylesterase, an enzyme involved in the metabolism of certain organophosphorus compounds. To better predict the efficacy of novel MCMs against CWNA exposure in human casualties, it is crucial to use appropriate animal models that mirror the human condition. We present a comprehensive characterization of the seizurogenic, epileptogenic, and neuropathologic effects of GD exposure with delayed anticonvulsant treatment in the plasma carboxylesterase knockout (ES1−/−) mouse.MethodsElectroencephalography (EEG) electrode‐implanted ES1−/− and wild‐type (C57BL/6) mice were exposed to various seizure‐inducing doses of GD, treated with atropine sulfate and the oxime HI‐6 at 1 minute after exposure, and administered midazolam at 15‐30 minutes following the onset of seizure activity. The latency of acute seizure onset and spontaneous recurrent seizures (SRS) was assessed, as were changes in EEG power spectra. At 2 weeks after GD exposure, neurodegeneration and neuroinflammation were assessed.Results GD‐exposed ES1−/− mice displayed a dose‐dependent response in seizure severity. Only ES1−/− mice exposed to the highest tested dose of GD developed SE, subchronic alterations in EEG power spectra, and SRS. Degree of neuronal cell loss and neuroinflammation were dose‐dependent; no significant neuropathology was observed in C57BL/6 mice or ES1−/− mice exposed to lower GD doses.SignificanceThe US Food and Drug Administration (FDA) animal rule requires the use of relevant animal models for the advancement of MCMs against CWNAs. We present evidence that argues for the use of the ES1−/− mouse model to screen anticonvulsant, antiepileptic, and/or neuroprotective drugs against GD‐induced toxicity, as well as to identify mechanisms of GD‐induced epileptogenesis.