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Objective PCDH19-related epilepsy is characterized by a distinctive pattern of X-linked inheritance, where heterozygous females exhibit seizures and hemizygous males are asymptomatic. A cellular interference mechanism resulting from the presence of both wild-type and mutant PCDH19 neurons in heterozygous patients or mosaic carriers of PCDH19 variants has been hypothesized. We aim to investigate seizure susceptibility and progression in the Pchd19 mouse model. Methods We assessed seizure susceptibility and progression in the Pcdh19 mouse model using three acute seizure induction paradigms. We first induced focal, clonic seizures using the 6-Hz psychomotor test. Mice were stimulated with increasing current intensities and graded according to a modified Racine scale. We next induced generalized seizures using flurothyl or pentylenetetrazol (PTZ), both γ-aminobutyric acid type A receptor function inhibitors, and recorded latencies to myoclonic and generalized tonic-clonic seizures. Results Pcdh19 knockout and heterozygous females displayed increased seizure susceptibility across all current intensities in the 6-Hz psychomotor test, and increased severity overall. They also exhibited shorter latencies to generalized seizures following flurothyl, but not PTZ, seizure induction. Hemizygous males showed comparable seizure incidence and severity to their wild-type male littermates across all paradigms tested. Significance The heightened susceptibility observed in Pcdh19 knockout females suggests additional mechanisms other than cellular interference are at play in PCDH19-related epilepsy. Further experiments are needed to understand the variability in seizure susceptibility so that this model can be best utilized toward development of future therapeutic strategies for PCDH19-related epilepsy.

A rapidly growing body of evidence supports the premise that neuroinflammation plays an important role in initiating and sustaining seizures in a range of pediatric epilepsies. Clinical and experimental evidence indicates that neuroinflammation is both an outcome and a contributor to seizures. In this manner, seizures that arise from an initial insult (e.g., infection, trauma, and genetic mutation) contribute to an inflammatory response that subsequently promotes recurrent seizures. This cyclic relationship between seizures and neuroinflammation has been described as a “vicious cycle.” Studies of human tissue resected for surgical treatment of refractory epilepsy have reported activated inflammatory and immune signaling pathways, while animal models have been used to demonstrate that key inflammatory mediators lead to increased seizure susceptibility. Further characterization of the molecular mechanisms involved in this cycle may ultimately enable the development of new therapeutic approaches for the treatment of epilepsy. In this brief review, we focus on key inflammatory mediators that have become prominent in recent literature of epilepsy, including newly characterized microRNAs and their potential role in neuroinflammatory signaling.

Neuroprotective and antiepileptogenic therapies have been extensively investigated for epilepsy prevention and treatment. This review gives an overview of the promising contribution of the ketogenic diet, a complementary treatment, on the intestinal microbiota to reduce seizure susceptibility. Next, the relevance of physical exercise is extensively addressed as a complementary therapy to reduce seizure susceptibility, and thereby impact beneficially on the epilepsy condition. In this context, particular attention is given to the potential risks and benefits of physical exercise, possible precipitant factors related to exercise and proposed mechanisms by which exercise can reduce seizures, and its antiepileptogenic effects. Finally, this review points to emerging evidence of exercise reducing comorbidities from epilepsy and improving the quality of life of people with epilepsy. Based on evidence from current literature, physical or sport activities represent a potential non-pharmacological intervention that can be integrated with conventional therapy for epilepsy.

Extensive activation of glial cells during a latent period has been well documented in various animal models of epilepsy; however, it remains unknown whether such glial activation is capable of promoting epileptogenesis. Here, we show that temporally distinct activation profiles of microglia and astrocytes collaboratively contribute to epileptogenesis in a drug-induced status epilepticus model. We found that reactive microglia appear first, followed by reactive astrocytes and increased susceptibility to seizures. Pharmacological intervention against microglial activation reduces astrogliosis, aberrant astrocyte Ca2+signaling, and seizure susceptibility. Reactive astrocytes exhibit larger Ca2+signals mediated by IP3R2, whereas deletion of this type of Ca2+signaling reduces seizure susceptibility after status epilepticus. Together, our findings indicate that the sequential activation of glial cells constitutes a cause of epileptogenesis after status epilepticus.

There is a ongoing debate whether generic early warning signals for critical transitions exist that can be applied across diverse systems. The human epileptic brain is often considered as a prototypical system, given the devastating and, at times, even life-threatening nature of the extreme event epileptic seizure. More than three decades of international effort has successfully identified predictors of imminent seizures. However, the suitability of typically applied early warning indicators for critical slowing down, namely variance and lag-1 autocorrelation, for indexing seizure susceptibility is still controversially discussed. Here, we investigated long-term, multichannel recordings of brain dynamics from 28 subjects with epilepsy. Using a surrogate-based evaluation procedure of sensitivity and specificity of time-resolved estimates of early warning indicators, we found no evidence for critical slowing down prior to 105 epileptic seizures., Comment: 6 pages, 3 figures

The human brain has the capacity to rapidly change state, and in epilepsy these state changes can be catastrophic, resulting in loss of consciousness, injury and even death. Theoretical interpretations considering the brain as a dynamical system would suggest that prior to a seizure recorded brain signals may exhibit critical slowing, a warning signal preceding many critical transitions in dynamical systems. Using long-term intracranial electroencephalography (iEEG) recordings from fourteen patients with focal epilepsy, we found key signatures of critical slowing prior to seizures. Signals related to a critically slowing process fluctuated over temporally long scales (hours to days), longer than would be detectable in standard clinical evaluation settings. Seizure risk was associated with a combination of these signals together with epileptiform discharges. These results provide strong validation of theoretical models and demonstrate that critical slowing is a reliable indicator that could be used in seizure forecasting algorithms.

Shank3, a postsynaptic scaffolding protein involved in regulating excitatory synapse assembly and function, has been implicated in several brain disorders, including autism spectrum disorders (ASD), Phelan-McDermid syndrome, schizophrenia, intellectual disability, and mania. Here we generated and characterized a Shank3 knock-in mouse line carrying the Q321R mutation (Shank3Q321R mice) identified in a human individual with ASD that affects the ankyrin repeat region (ARR) domain of the Shank3 protein. Homozygous Shank3Q321R/Q321R mice show a selective decrease in the level of Shank3a, an ARR-containing protein variant, but not other variants. CA1 pyramidal neurons in the Shank3Q321R/Q321R hippocampus show decreased neuronal excitability but normal excitatory and inhibitory synaptic transmission. Behaviorally, Shank3Q321R/Q321R mice show moderately enhanced self-grooming and anxiolytic-like behavior, but normal locomotion, social interaction, and object recognition and contextual fear memory. In addition, these mice show abnormal electroencephalogram (EEG) patterns and decreased susceptibility to induced seizures. These results indicate that the Q321R mutation alters Shank3 protein stability, neuronal excitability, repetitive and anxiety-like behavior, EEG patterns, and seizure susceptibility in mice.

The human brain, largely accepted as the most complex biological system known, is still far from being understood in its parts or as a whole. More specifically, biological mechanisms of epileptic states and state transitions are not well understood. Here, we explore the concept of the epilepsy as a manifestation of a multistate network composed of coupled oscillatory units. We also propose that functional coupling between neuroglial elements is a dynamic process, characterized by temporal changes both at short and long time scales. We review various experimental and modelling data suggesting that epilepsy is a pathological manifestation of such a multistate network – both when viewed as a coupled oscillatory network, and as a system of multistate stable state attractors. Based on a coupled oscillators model, we propose a significant role for glial cells in modulating hyperexcitability of the neuroglial networks of the brain. Also, using these concepts, we explain a number of observable phenomena such as propagation patterns of bursts within a seizure in the isolated intact hippocampus in vitro, postictal generalized suppression in human encephalographic seizure data, and changes in seizure susceptibility in epileptic patients. Based on our conceptual model we propose potential clinical applications to estimate brain closeness to ictal transition by means of active perturbations and passive measures during on-going activity.

Objective The aim of this study was to investigate the effects of pre-pregnancy chronic exposure to Porphyromonas gingivalis LPS (Pg LPS) on the learning, memory, and seizure susceptibility of the offspring. Design To achieve periodontitis, Pg LPS (5 μg/kg) was injected into the gingival of five female rats every 48 h for three weeks. Five control female rats received saline (0.9 %) and five female were kept intact. The concentrations of TNF-α and IL-6 were measured in the blood samples. One week after the final injection, females were mated with intact males. Following birth and weaning, two male and two female offspring were randomly selected from each mother, and new groups of male and female offspring were defined for behavioral assessments. Morris water maze was used to evaluate spatial memory, shuttle box was used to investigate avoidance memory and a pentylenetetrazole-induced seizure was used to evaluate seizure susceptibility in the offspring. Results Spatial learning and avoidance memory significantly decreased in both male and female offspring of Pg LPS-exposed female rats, compared to the control offspring. Latency to reach seizure stages 1 and 2 significantly increased in the male offspring, but not the female offspring of Pg LPS-exposed female, compared to the control offspring. However, no significant difference was found in latency to reach stages 3–5. Conclusion Pre-pregnancy exposure to Pg LPS could affect some behavioral functions in both male and female offspring intergenerationally.

Mounting evidence suggests that modulation of cannabinoid 2 receptors (CB2Rs) is therapeutic in mouse models of neurological disorders, including neuropathic pain, neurodegenerative disease, and stroke. We previously showed that reducing CB2R activity increases seizure susceptibility in mice. In the present study, we evaluated the therapeutic potential of the CB2R positive allosteric modulator, Ec21a, against induced seizures in mice. The pharmacokinetic profile of Ec21 demonstrated a similar distribution in brain and plasma, with detection up to 12 h following injection. Ec21a increased resistance to induced seizures in CF1 wild-type mice and mice harboring the SCN1A R1648H human epilepsy mutation. A rotarod test provided evidence that Ec21a does not cause neurotoxicity-induced motor deficits at its therapeutic dose, and seizure protection was maintained with repeated drug administration. The selectivity of Ec21a for CB2R was supported by the ability of the CB2R antagonist AM630, but not the CB1R antagonist AM251, to block Ec21a-conferred seizure protection in mice, and a lack of significant binding of Ec21a to 34 brain-expressed receptors and transporters in vitro. These results identify allosteric modulation of CB2Rs as a promising therapeutic approach for the treatment of epilepsy.

Status epilepticus is the most common serious neurological condition triggered by abnormal electrical activity, leading to severe and widespread cell loss in the brain. Lithium has been one of the main drugs used for the treatment of bipolar disorder for decades, and its anticonvulsant and neuroprotective properties have been described in several neurological disease models. However, the therapeutic mechanisms underlying lithium's actions remain poorly understood. The muscarinic receptor agonist pilocarpine is used to induce status epilepticus, which is followed by hippocampal damage. The present study was designed to investigate the effects of lithium post-treatment on seizure susceptibility and hippocampal neuropathological changes following pilocarpine-induced status epilepticus. Status epilepticus was induced by administration of pilocarpine hydrochloride (320 mg/kg, i.p.) in C57BL/6 mice at 8 weeks of age. Lithium (80 mg/kg, i.p.) was administered 15 minutes after the pilocarpine injection. After the lithium injection, status epilepticus onset time and mortality were recorded. Lithium significantly delayed the onset time of status epilepticus and reduced mortality compared to the vehicle-treated group. Moreover, lithium effectively blocked pilocarpine-induced neuronal death in the hippocampus as estimated by cresyl violet and Fluoro-Jade B staining. However, lithium did not reduce glial activation following pilocarpine-induced status epilepticus. These results suggest that lithium has a neuroprotective effect and would be useful in the treatment of neurological disorders, in particular status epilepticus.

There is substantial evidence in rodent models that chronic exposure to cannabinoids during adolescence can alter the development of neurobiological systems that are implicated in regulating brain activity and seizure. The current study explored whether adolescent cannabinoid treatment affects subsequent, adult seizure susceptibility. Sixty male Wistar Kyoto rats were treated with either the synthetic cannabinoid, CP 55,940 (0.4mg/kg, one treatment per day), or vehicle between 35 and 45days old. Subjects were then allowed to mature to adulthood. At 68-69days of age, subjects were tested for seizure susceptibility using the pro-convulsant, pentylenetetrazol (PTZ). Subjects received an acute injection of either 35mg/kg or 50mg/kg PTZ immediately prior to a 30-min behavioral seizure test. PTZ doses were chosen to produce low-to-moderate levels of seizure activity in control subjects. There were no significant differences between treated and control subjects in: latency to first seizure, mean seizure severity, percentage who displayed any seizure activity, percentage who displayed clonic seizure, or percentage who displayed tonic-clonic seizure. However, CP 55,940-treated subjects had a higher mortality rate compared to controls at both PTZ doses, suggesting that adolescent cannabinoid exposure may increase the lethality of severe seizures experienced in adulthood.

Epilepsy is a common neurological disease, affecting 2.4 million people in the US. Among the many different forms of the disease, temporal lobe epilepsy (TLE) is one of the most frequent in adults. Recent studies indicate the presence of a hyperactive hypothalamopituitary- adrenocortical (HPA) axis and elevated levels of glucocorticoids in TLE patients. Moreover, in these patients, stress is a commonly reported trigger of seizures, and stress-related psychopathologies, including depression and anxiety, are highly prevalent. Elevated glucocorticoids have been implicated in the development of stress-related psychopathologies. Similarly, excess glucocorticoids have been found to increase neuronal excitability, epileptiform activity and seizure susceptibility. Thus, patients with TLE may generate abnormal stress responses that both facilitate ictal discharges and increase vulnerability for the development of comorbid psychopathologies. Here, we will examine the evidence that the HPA axis is disrupted in TLE, consider potential mechanisms by which this might occur, and discuss the implications of HPA dysfunction for seizuretriggering and psychiatric comorbidities.

Atypical febrile seizures are considered a risk factor for epilepsy onset and cognitive impairments later in life. Patients with temporal lobe epilepsy and a history of atypical febrile seizures often carry a cortical malformation. This association has led to the hypothesis that the presence of a cortical dysplasia exacerbates febrile seizures in infancy, in turn increasing the risk for neurological sequelae. The mechanisms linking these events are currently poorly understood. Potassium-chloride cotransporter KCC2 affects several aspects of neuronal circuit development and function, by modulating GABAergic transmission and excitatory synapse formation. Recent data suggest that KCC2 downregulation contributes to seizure generation in the epileptic adult brain, but its role in the developing brain is still controversial. In a rodent model of atypical febrile seizures, combining a cortical dysplasia and hyperthermia-induced seizures (LHS rats), we found a premature and sustained increase in KCC2 protein levels, accompanied by a negative shift of the reversal potential of GABA. In parallel, we observed a significant reduction in dendritic spine size and mEPSC amplitude in CA1 pyramidal neurons, accompanied by spatial memory deficits. To investigate whether KCC2 premature overexpression plays a role in seizure susceptibility and synaptic alterations, we reduced KCC2 expression selectively in hippocampal pyramidal neurons by in utero electroporation of shRNA. Remarkably, KCC2 shRNA-electroporated LHS rats show reduced hyperthermia-induced seizure susceptibility, while dendritic spine size deficits were rescued. Our findings demonstrate that KCC2 overexpression in a compromised developing brain increases febrile seizure susceptibility and contribute to dendritic spine alterations.

Various Drosophila models of human disease have recently received increased interest. The main goal is to uncover the fundamental biological basis for human pathology taking advantage of the power of Drosophila genetics. This review examines a set of Drosophila seizure-sensitive mutations that model human seizure disorders, especially epilepsy. Also described is a novel set of mutations that act as seizure-suppressors that ameliorate epilepsy phenotypes in double mutant combinations.

SUMMARY The anterior thalamus (AT) is critical for memory formation, processing navigational information, and seizure initiation. However, the molecular mechanisms that regulate synaptic function of AT neurons remain largely unexplored. We report that AMPA receptor auxiliary subunit GSG1L controls short-term plasticity in AT synapses that receive inputs from the cortex, but not in those receiving inputs from other pathways. A canonical auxiliary subunit stargazin co-exists in these neurons but is functionally absent from corticothalamic synapses. In GSG1L knockout mice, AT neurons exhibit hyperexcitability and the animals have increased susceptibility to seizures, consistent with a negative regulatory role of GSG1L. We hypothesize that negative regulation of synaptic function by GSG1L plays a critical role in maintaining optimal excitation in the AT., Graphical Abstract, In Brief Kamalova et al. report the phenotypes of GSG1L KO mice. The synaptic function of AMPAR auxiliary subunit GSG1L in the anterior thalamus is input specific. GSG1L suppresses short-term facilitation and decreases AMPAR activity specifically in corticothalamic synapses, where stargazin is functionally absent. GSG1L KO mice exhibit hyperexcitability and seizure susceptibility.

KCNQ2/3 channels, ubiquitously expressed neuronal potassium channels, have emerged as indispensable regulators of brain network activity. Despite their critical role in brain homeostasis, the mechanisms by which KCNQ2/3 dysfunction lead to hypersychrony are not fully known. Here, we show that deletion of KCNQ2/3 channels changed PV+ interneurons’, but not SST+ interneurons’, firing properties. We also find that deletion of either KCNQ2/3 or KCNQ2 channels from PV+ interneurons led to elevated homeostatic potentiation of fast excitatory transmission in pyramidal neurons. Pvalb-Kcnq2 null-mice showed increased seizure susceptibility, suggesting that decreases in interneuron KCNQ2/3 activity remodels excitatory networks, providing a new function for these channels.

Shen et al. demonstrate a developmental role of astrocytes in shaping a predisposition to seizure generation. Activation of TLR4–MyD88–ERK1/2 signaling pathway in astrocytes during a critical postnatal period promotes excitatory synapse generation, leading to enhanced seizure susceptibility., Astrocytes are critical in synapse development, and their dysfunction in crucial developmental stages leads to serious neurodevelopmental diseases, including seizures and epilepsy. Immune challenges not only affect brain development, but also promote seizure generation and epileptogenesis, implying immune activation is one of the key factors linking seizures and epilepsy to abnormal brain development. In this study, we report that activating astrocytes by systemic lipopolysaccharide (LPS) challenges in the second postnatal week promotes excitatory synapse development, leading to enhanced seizure susceptibility in mice. Toll-like receptor 4 (TLR4) activation in astrocytes increased astrocytic extracellular signal–related kinase 1/2 (Erk1/2) and phospho-Erk1/2 levels in a myeloid differentiation primary response protein 88 (MyD88)–dependent manner. Constitutively activating Erk1/2 in astrocytes was sufficient to enhance excitatory synaptogenesis without activating TLR4. Deleting MyD88 or suppressing Erk1/2 in astrocytes rescued LPS-induced developmental abnormalities of excitatory synapses and restored the enhanced seizure sensitivity. Thus, we provide direct evidence for a developmental role of astrocytes in shaping a predisposition to seizure generation.

Previous studies showed that the glyoxalase 1 (Glo1) gene modulates anxiety-like behavior, seizure susceptibility, depression-like behavior, and alcohol drinking in the drinking-in-the-dark paradigm in nondependent mice. Administration of the small-molecule GLO1 inhibitor S-bromobenzylglutathione cyclopentyl diester (pBBG) decreased alcohol drinking in nondependent mice, suggesting a possible therapeutic strategy. However, the preclinical therapeutic efficacy of pBBG in animal models of alcohol dependence remains to be demonstrated. We tested the effect of pBBG (7.5 and 25 mg/kg) on operant alcohol self-administration in alcohol-dependent and nondependent rats. Wistar rats were trained to self-administer 10% alcohol (v/v) and made dependent by chronic intermittent passive exposure to alcohol vapor for 5 weeks. Pretreatment with pBBG dose-dependently reduced alcohol self-administration in both nondependent and dependent animals, without affecting water self-administration. pBBG treatment was more effective in dependent rats than in nondependent rats. These data extend previous findings that implicated Glo1 in alcohol drinking in nondependent mice by showing even more profound effects in alcohol-dependent rats. These results suggest that the pharmacological inhibition of GLO1 is a relevant therapeutic target for the treatment of alcohol use disorders.HighlightsAlcohol use disorder (AUD) places an enormous burden on society, and there is an urgent need for new druggable targets.Glo1 inhibition by pBBG dose-dependently reduces alcohol self-administration in both nondependent and dependent animals.pBBG treatment is more effective in reducing alcohol intake in dependent rats than in nondependent rats.

AIMS Intracellular calcium plays an important role in neuronal hyperexcitability that leads to seizures. One calcium influx route of interest is the transient receptor potential vanilloid type 1 (TRPV1) channel. Here, we evaluated the effects of capsazepine (CPZ), a potent blocker of TRPV1 channels on acoustically evoked seizures (audiogenic seizures, AGS) in the genetically epilepsy-prone rat (GEPR-3), a model of inherited epilepsy. METHODS Male and female GEPR-3s were used. For the acute CPZ treatment study, GEPR-3s were tested for AGS susceptibility before and after treatment with various doses of CPZ (0, 1, 3, and 10 mg/kg; ip). For semichronic CPZ treatment study, GEPR-3s were tested for AGS susceptibility before and after 5-day CPZ treatment at the dose of 1 mg/kg (ip). The prevalence, latency, and severity of AGS were recorded and analyzed. RESULTS We found that acute CPZ pretreatment reduced the seizure severity in male GEPR-3s; the effect was dose-dependent. In female GEPR-3s, however, CPZ treatment completely suppressed the seizure susceptibility. Furthermore, semichronic CPZ treatment suppressed seizure susceptibility in female GEPR-3s, but only reduced the seizure severity in male GEPR-3s. CONCLUSIONS These findings suggest that the TRPV1 channel is a promising molecular target for seizure suppression, with female GEPR-3s exhibiting higher sensitivity than male GEPR-3s.

Alzheimer's disease is a common age associated neurodegenerative disorder associated with an elevated risk of seizures that may be fundamentally connected to cognitive dysfunction. We used 4-9month-old mice of the APP/PS1 mouse model of Alzheimer's disease to study the presence of epileptiform-like discharges and to establish if the amyloid-β plaques affect their generation. The EEG of the APP/PS1 transgenic mice revealed a higher incidence of epileptiform-like discharges i.e. seizure events (interictal spikes, sharp waves, or polyspikes) than in the controls. Also, APP/PS1 mice showed a lower latency to evoke seizure events than in the control animals when pentylenetetrazole (60mg/kg; i.p.) was injected. Moreover, physostigmine injection (1mg/kg; i.p.) also increased the frequency of spontaneous epileptiform-like discharges in the APP/PS1 mice. We also found a correlation between the frequency of epileptiform-like discharges and the number of amyloid-β plaques. Application of N-(2-chloroethyl)-N-ethyl-bromobenzylamine (50mg/kg) generated amyloid-β plaques in the cortex and seizure activity appeared. Taken together, these data indicate that deposits of amyloid-β plaques may be responsible for the epileptiform-like discharges recorded in the APP/PS1 mice and could be responsible for the elevated risk for seizures of Alzheimer's patients.

Treatment of TBI remains a major unmet medical need, with 2.5 million new cases of traumatic brain injury (TBI) each year in Europe and 1.5 million in the USA. This single-center proof-of-concept preclinical study tested the hypothesis that pharmacologic neurostimulation with proconvulsants, either atipamezole, a selective α2-adrenoceptor antagonist, or the cannabinoid receptor 1 antagonist SR141716A, as monotherapy would improve functional recovery after TBI. A total of 404 adult Sprague-Dawley male rats were randomized into two groups: sham-injured or lateral fluid-percussion–induced TBI. The rats were treated with atipamezole (started at 30 min or 7 d after TBI) or SR141716A (2 min or 30 min post-TBI) for up to 9 wk. Total follow-up time was 14 wk after treatment initiation. Outcome measures included motor (composite neuroscore, beam-walking) and cognitive performance (Morris water-maze), seizure susceptibility, spontaneous seizures, and cortical and hippocampal pathology. All injured rats exhibited similar impairment in the neuroscore and beam-walking tests at 2 d post-TBI. Atipamezole treatment initiated at either 30 min or 7 d post-TBI and continued for 9 wk via subcutaneous osmotic minipumps improved performance in both the neuroscore and beam-walking tests, but not in the Morris water-maze spatial learning and memory test. Atipamezole treatment initiated at 7 d post-TBI also reduced seizure susceptibility in the pentylenetetrazol test 14 wk after treatment initiation, although it did not prevent the development of epilepsy. SR141716A administered as a single dose at 2 min post-TBI or initiated at 30 min post-TBI and continued for 9 wk had no recovery-enhancing or antiepileptogenic effects. Mechanistic studies to assess the α2-adrenoceptor subtype specificity of the disease-modifying effects of atipametzole revealed that genetic ablation of α2A-noradrenergic receptor function in Adra2A mice carrying an N79P point mutation had antiepileptogenic effects after TBI. On the other hand, blockade of α2C-adrenoceptors using the receptor subtype-specific antagonist ORM-12741 had no favorable effects on the post-TBI outcome. Finally, to assess whether regulation of the post-injury inflammatory response by atipametzole in glial cells contributed to a favorable outcome, we investigated the effect of atipamezole on spontaneous and/or lipopolysaccharide-stimulated astroglial or microglial cytokine release in vitro. We observed no effect. Our data demonstrate that a 9-wk administration of α2A-noradrenergic antagonist, atipamezole, is recovery-enhancing after TBI., final draft, peerReviewed

According to the World Health Organization, 50 million people worldwide have epilepsy. Traumatic brain injury (TBI) is estimated to cause 10%–20% of all of symptomatic epilepsies, and 5% of all epilepsies. Over the past 15 years, several laboratories have reported spontaneous seizures after inducing TBI in rats and mice. The TBI models in which spontaneous seizures are detected include fluid percussion injury, and controlled cortical impact models. Increased seizure susceptibility has also been described in a weight-drop model. Recent studies identified some genotypes that predispose to post-TBI epileptogenesis or comorbidogenesis. The use of post-TBI models in antiseizure drug-discovery is rare, but they have been used in more than 10 proof-of-concept preclinical antiepileptogenesis trials in an attempt to find treatments to alleviate the development of post-TBI epilepsy and comorbidities. Despite significant progress in modeling posttraumatic epileptogenesis, the animal models still represent only a few of the injury types and pathologies of patients with TBI destined to develop epilepsy. Also, experimental studies investigating posttraumatic epileptogenesis in young or old animals, as well as in females, are lacking. Endophenotyping human epileptogenic TBI is critical for the advancement of preclinical model development.

Kindling was first recognized in 1968 by Graham Goddard during experiments investigating whether learning in rats was disrupted by repeated hippocampal electrical stimulation. Goddard observed that repeated electrical stimulation of a variety of brain pathways unexpectedly evoked gradually evolving seizures and permanent progressive increases in seizure susceptibility that he described as “kindling,” and recognized as potentially significant for epilepsy.

Genetic Generalized Epilepsy (GGE) encompasses two well-studied syndrome specific epilepsies. Here we discuss recent advances in our understanding of mouse models of Generalized Epilepsy with Febrile Seizures plus (GEFS+) and Dravet syndrome. This disease spectrum includes individuals with a broad range of clinical features, from mildly to severely affected, and often associated with the same genetic mutation. Insight gained through the analyses of genetic mouse models have advanced our understanding of the mechanisms that transform monogenic lesions to cell-type specific, network, and whole brain dysfunction. Growing evidence suggests that while ion channel gene mutations are primarily linked to seizure genesis, structural changes are also evident and may contribute to epileptogenesis, including increased seizure susceptibility and disease severity.

There are reports of sex differences in epilepsy with respect to incidence, progression and severity of the disease, response to therapy, and occurrence of adverse drug effects. Thus, it is necessary to design sex-specific treatment strategies. Similarly, more animal studies are needed to determine the underlying mechanisms for sex differences in seizure susceptibility. Preclinical testing of antiepileptic drugs should include separate sex-specific testing to determine the effectiveness or possible adverse effects in males and females.

It is becoming increasingly clear that the genetic background of mice and rats, even in inbred strains, can have a profound influence on measures of seizure susceptibility and epilepsy. These differences can be capitalized upon through genetic mapping studies to reveal genes important for seizures and epilepsy. In this chapter, we discuss findings related to how this genetic heterogeneity has been (and can be) utilized in the epilepsy field to reveal novel insights into seizures and epilepsy. Moreover, we discuss how caution is needed with regard to rodent strain or even animal vendor choice, and how this can significantly influence seizure and epilepsy parameters in unexpected ways. This is particularly critical in decisions regarding the strain of choice used in generating mice with targeted deletions of genes.