Biology subjects

Barker-Haliski, M.

Publications and source records attributed to Barker-Haliski, M..

13 recordsLinked to original sources

bioRxiv2026

Pregnancy History and Loss of Normal PSEN2 Function Impact Female Late-Life Cognitive Processing, Inhibitory Signaling, and Gliosis

Background. Alzheimer's disease (AD) is well-documented to be more progressive in affected females. It is thus critical to define how female-specific life experiences interact with AD-related risk factors to impact disease trajectory and functional burden. For example, pregnancy exerts dramatic influences on the maternal immune system, behavior, and neuroplasticity, specifically in hippocampal and limbic structures. The long-term clinical impacts from pregnancy history (parity) on late-life AD outcomes are, however, conflicting. Thus, we investigated the late-life functional impacts of parity on rodent cognitive function, inhibitory neuron density, and glial biology with loss of normal function of the AD-related risk factor, presenilin 2 (PSEN2). Methods. Female PSEN2 knockout (KO) and wild-type (WT) mice with (multiparous) and without (nulliparous) pregnancy history were challenged at 10-15 months-old in the T-maze (TM) and Open Field Test (OFT), followed by immunofluorescence for neuronal signaling and gliosis markers. Results. Neither parity history nor PSEN2 deficiency impacted hippocampally-mediated spatial working memory of aged female mice in the TM. However, both PSEN2 KO and multiparous mice exhibited decreased OFT locomotor behavior. Multiparous mice also showed reduced OFT center zone exploration (p=0.0045) suggesting a more anxious phenotype. Parity history generally increased inhibitory marker expression in dorsal hippocampus (p=0.017), prefrontal cortex (p=0.021), and amygdala (p=0.035). Parity generally blunted oligodendrocyte marker expression in CA1 (p<0.05), while boosting astrocyte and microglia marker expression in CA3 of dorsal hippocampus. Conclusion. This work suggests that although parity history and PSEN2 deficiency exert individual differing age-related effects on cognition and neurobiology, they do not act synergistically.

neuroscience↗

bioRxiv2026

A Humanized Mouse Model of DRPLA Recapitulates Epilepsy and Demonstrates Antisense Oligonucleotide-Mediated Disease Modification

Dentatorubral-pallidoluysian atrophy (DRPLA) is an ultra-rare progressive myoclonus epilepsy caused by a glutamine-coding CAG repeat expansion in atrophin-1 (ATN1). Mutant ATN1 (mATN1) expression results in symptoms that inversely correlate to CAG-expansion size: young-onset cases have the most CAG repeats and developmental delay, high-frequency treatment-resistant seizures, and early mortality. We sought to characterize the seizure susceptibility of a fully humanized ATN1 mouse expressing human mATN1 with 112 CAG repeats to then assess therapeutic antisense oligonucleotide (ASO) intervention on seizure-related outcomes. Atn1Q112/+ or wild-type (WT) mice were treated with investigational ASO targeting human, CAG-expanded, ATN1 or saline (P2 and then again at 4 weeks-old) before acute seizure testing, ataxia profiling, and chronic in vivo video-EEG recording for spontaneous seizures up to 8 weeks-old. Saline-treated Atn1Q112/+ mice were more seizure prone with early death. However, ASO administration to Atn1Q112/+ mice normalized seizure threshold, decreased ataxia, and protected against early death. Atn1Q112/+ mice exhibited spontaneous behavioral seizures recorded over 2 weeks, which were absent in ASO-treated Atn1Q112/+ and WT mice, with a specific mATN1 expression-driven decrease in delta and theta EEG frequencies. Atn1Q112/+ mice are highly seizure prone, validating this model for DRPLA epilepsy. ATN1 represents a novel epilepsy-related risk factor for therapeutic investigation.

neuroscience↗

bioRxiv2025

Loss of presenilin 2 function age-dependently increases susceptibility to kainate-induced acute seizures and blunts hippocampal kainate-type glutamate receptor expression

Presenilin 2 (PSEN2) variants increase risk of Alzheimers disease (AD) and unprovoked seizures. Yet, age-related PSEN2 contributions to seizure susceptibility are understudied. Critically, PSEN proteolytic capacity may regulate hippocampal kainate-type glutamate receptor (KARs) availability. Kainic acid (KA) is a KAR agonist that evokes severe seizures in mice. We hypothesized that PSEN2 knockout (KO) mice would show reduced latency to KA-induced seizures, increased seizure burden, worsened 7-day survival, and altered hippocampal KAR expression compared to wild-type (WT) controls. Using repeated low-dose systemic KA administration to 3-4- and 12-15-month-old PSEN2 KO versus WT mice, we quantified acute seizure latency and neuropathology. GluK2 and GluK5 KAR subunit expression was colocalized in astrocytes 7 days after seizures or sham to assess the impact of PSEN2 loss and seizures on hippocampal KARs. Young PSEN2 KO mice were more seizure-prone than WTs, while genotype did not change latency to first seizure. Aged females seized faster than young females and experienced greater mortality, unlike males. There was no difference in KAR subunit expression between young mouse genotypes and regardless of seizure history. In both genotypes, hippocampal CA3 astrocytes expressed GluK5 after seizures, however, astrocytic GluK2 upregulation only occurred in WTs. GluK5 expression was significantly reduced in aged seizure-naive PSEN2 KO versus WT mice, while total GluK2 expression did not differ. Seizure-induced astrocytic GluK5 expression only occurred in WT mice in CA3, while astrocytic GluK2 expression occurred in both. Thus, PSEN2 loss may impair age-related hippocampal KAR expression, implicating KARs as understudied contributors to AD-related seizures. Highlights.- Alzheimers disease (AD) and epilepsy share many pathophysiological links, but the contributions of distinct AD-risk factors are understudied. - Loss of normal presenilin 2 function is associated with AD; its role in late-life seizures and neuropathology have been minimally evaluated. - Loss of presenilin 2 increases susceptibility to kainic-acid induced acute seizures in young adult mice, mirroring late life risk. - Increased susceptibility to kainic acid induced acute seizures due to loss of PSEN2 is lost in late life, suggesting earlier senescence. - Loss of presenilin 2 function in aged mice is associated with reduced GluK5 expression and greater astrogliosis under basal conditions.

neuroscience↗

bioRxiv2025

Impact of Dysbiosis and Antiseizure Medication on Seizure Pathophysiology in a Viral Infection-Induced Epilepsy Model

Viral encephalitis is a major worldwide cause of acquired epilepsy, yet the impact of environmental and non-neuronal factors on an individuals risk for epilepsy is understudied. For example, the gut microbiome influences immune system function yet the impact of the gut microbiome on seizure-associated neuropathology remains poorly understood. Using the Theilers murine encephalomyelitis virus (TMEV) mouse model of infection-induced acute symptomatic seizures (ASyS), we aimed to investigate how antibiotic (ABX)-induced gut dysbiosis during a brain viral infection could influence resulting hippocampal neuropathology. Further, we included co-administration of carbamazepine (CBZ) to assess the extent to which antiseizure medicines could also shift the neurological impact of ASyS and gut dysbiosis. Brain tissue from TMEV-infected mice with and without gut dysbiosis was assessed for neurodegeneration and glial response (astrocytes and microglia). TMEV infection primarily drove neuroinflammatory changes in CA1, including increased astrogliosis, microgliosis, and microglial activation. ABX-induced dysbiosis exacerbated neuroinflammation across hippocampal subregions, markedly increasing microgliosis in CA3 and DG, and elevating microglial and neuronal proliferation in CA1. TMEV infection-induced astrogliosis was impacted by dysbiosis in a region-dependent manner, being worsened in DG while being alleviated in CA3. CBZ was neuroprotective selectively within DG, reducing neurodegeneration and microglial immunoreactivity with dysbiosis. Astroglial proliferation occurred regardless of gut microbiome integrity. Altogether, gut dysbiosis shapes hippocampal neuroimmune responses following viral infection-induced ASyS in a region-dependent manner, and CBZ may confer a neuroprotective effect. Together this work highlights the acute neuroinflammatory impact of infection-induced ASyS and reveals an underappreciated contribution of the gut-brain-axis to seizure-related neuropathology.

neuroscience↗

bioRxiv2025

Atrophin-1 Antisense Oligonucleotide Provides Robust Protection from Pathology in a Fully Humanized DRPLA Model

Dentatorubral-pallidoluysian atrophy (DRPLA) is a fatal neurodegenerative disease arising from a CAG repeat expansion in the atrophin-1 (ATN1) gene. Because DRPLA, like many repeat expansion disorders (REDs), arises predominantly from toxic gain-of-function mechanisms, we hypothesized that ATN1 knockdown would have therapeutic potential. To test this, we established the first fully-humanized mouse model of a RED, in which one allele of mouse Atn1 is completely replaced by human ATN1, including 112 pure CAG repeats. This novel approach to exploring RED biology provides significant advantages, notably the ability to test sequence-specific therapeutics targeting human sequences, even in introns and untranslated regions of pre-mRNA. We found that our model--the Atn1Q112/+ mouse--recapitulates key features of human DRPLA, including behavioral alterations, reduced brain size and aggregate accumulation. We treated Atn1Q112/+ mice with antisense oligonucleotides (ASOs) targeting mouse Atn1 (to probe for loss of function concerns), human ATN1, or a combination. Treatment with human, but not mouse, ATN1-targeting ASOs provides remarkable protection from a range of disease-related behavioral phenotypes, including aggregation of mutant ATN1 (mATN1), and marked rescue of transcriptional dysregulation in the cerebellum. These results have helped motivate an ongoing human clinical study of ASOs targeting ATN1 for DRPLA.

neuroscience↗

bioRxiv2025

Acute Dose-Related Effect of Antiseizure Medicines on Open Field Exploration of Male Rats with Established Epilepsy

Antiseizure medicines (ASMs) cause both acute and chronic behavioral side effects in individuals with epilepsy. While clinical and preclinical studies often focus on chronic effects, the acute dose-related impact of ASMs on behavior is underreported, especially in rodent temporal lobe epilepsy (TLE) models. Investigating the acute effects of both therapeutic and behaviorally impairing doses may inform clinically relevant adverse effects, such as sedation, hyperactivity, and impaired coordination, which are essential for evaluating drug safety and tolerability. This study investigated the acute effects of anticonvulsant doses of carbamazepine (CBZ), valproic acid (VPA), levetiracetam (LEV), and cenobamate (CNB) on locomotor activity and exploratory behavior in rats 8-13 weeks after kainic acid-induced status epilepticus to elicit confirmed spontaneous recurrent seizures consistent (SRS) with TLE. Behavioral outcomes were quantified using an automated open field task (OFT) in both epileptic and non-epileptic (naive) rats. Our findings revealed that anticonvulsant doses of CNB affected locomotor behavior while other ASMs did not alter exploratory behavior. However, the motor impairing doses of CBZ and CNB equally suppressed exploratory behavior, likely due to sedative effects, in both epileptic and non-epileptic rats. LEV was unique, showing no sedative effects even at high doses, while VPA exhibited an anxiolytic effect in SRS rats and a sedative effect in naive rats at high dose. This study provides essential insight into the efficacy and tolerability profiles of a diversity of FDA-approved ASMs in a clinically relevant TLE model. Thus, SRS may influence ASM tolerability in preclinical TLE models that may inform clinical translation.

animal behavior and cognition↗

bioRxiv2024

Intestinal Dysbiosis Alters Acute Seizure Burden and Antiseizure Medicine Activity in the Theiler's Virus Model of Encephalitis

ObjectiveBrain infection with Theilers virus (TMEV) in C57BL/6J mice produces an etiologically relevant model of acquired seizures. Dietary changes can modify acute seizure presentation following TMEV brain infection and influence intestinal microbiome diversity and composition. Intestinal dysbiosis may thus similarly affect seizure burden and antiseizure medicine (ASM) activity in this model, independent of pharmacokinetic effects. We thus sought to define the influence of antibiotic (ABX)-induced gut dysbiosis on acute seizure presentation, anticonvulsant activity of carbamazepine (CBZ), and CBZ pharmacokinetics with TMEV infection. MethodsMale C57BL/6J mice (4-5 weeks) received oral (p.o.) ABX or saline (SAL) once daily beginning on arrival through Day 7 post-TMEV infection (p.i.). Mice were infected with TMEV or PBS on Day 0. Mice received intraperitoneal (i.p.; 20 mg/kg) CBZ or vehicle (VEH) twice daily Days 3-7 p.i. and were assessed for handling-induced seizures 30 min after treatment. Plasma was collected on Day 7 p.i. at 15 and 60 min post-CBZ administration for bioanalysis. ResultsTMEV infection induced acute seizures, but ABX-induced gut dysbiosis altered seizure presentation. There were 75% SAL-VEH, 35% SAL-CBZ, 35% ABX-VEH, and 72% ABX- CBZ mice with seizures during the 7-day monitoring period. There was a significant pretreatment x ASM interaction (p=0.0001), with differences in seizure burden in SAL- versus ABX-pretreated mice (p=0.004). CBZ significantly increased latency to seizure presentation; an effect absent in ABX-CBZ mice. Plasma CBZ concentrations did not differ between SAL and ABX pretreatment groups, suggesting that ABX did not influence CBZ pharmacokinetics. SignificanceABX-induced gut dysbiosis markedly altered acute disease trajectory with TMEV- induced encephalitis, reflecting a novel contribution of the gut microbiome to seizure presentation. ABX-induced gut dysbiosis also significantly changed acute seizure control by CBZ, but did not influence plasma CBZ concentrations. The gut-brain axis is thus an under- recognized contributor to TMEV infection-induced seizures, ASM activity, and disease burden. Key PointsO_LITheilers virus infection in mice models encephalitis that exhibits differential disease trajectory with gut microbiome modulation. C_LIO_LIExperimentally evoked gut dysbiosis, i.e. a disrupted gut microbiome, dramatically shifts the anticonvulsant activity of carbamazepine. C_LIO_LIThere is no concomitant shift in circulating carbamazepine concentrations in TMEV- infected mice with and without a dysbiotic microbiome. C_LIO_LIThe gut microbiome is an under-recognized driver of seizure risk and antiseizure medicine activity in the Theilers virus mouse model. C_LI

neuroscience↗

bioRxiv2024

Repeated administration of pharmaceutical-grade medium chain triglycerides, a common pharmacologic excipient, confers dose-dependent toxicity by the intraperitoneal but not oral route in mice

Pharmaceutical-grade medium chain triglycerides (MCTs) are common excipients for in vivo pharmacological studies in laboratory animals, and as an experimental therapeutic in certain metabolic and neurological disorders. In this study, we examined the tolerability of repeated administration of a pharmaceutical-grade formulation of three MCTs--caprylic, capric, and lauric acid - in mice via the oral (PO) and intraperitoneal (IP) routes. We administered either 8 or 4 {micro}L of 100% MCTs or saline/gram of body weight twice daily for seven days. During administration and for seven days after, we monitored weight change and clinical presentation. On day 14, or upon meeting euthanasia criteria, animals were sacrificed for gross necropsy, histology, and complete blood count. We observed significant weight loss, clinical decline and 100% mortality in animals receiving 8 {micro}L/g of MCTs via the IP route of administration. Gross necropsy revealed serosanguinous fluid in the thoracic cavity, dark red mottled lungs, and adhesions in the abdominal cavity. Histology confirmed inflammation of the lungs, mediastinum, and peritoneum. Mild gross lesions and initial weight loss (through day 3) were also present in mice receiving 4 {micro}L/g of MCTs IP. However, these animals regained weight by day seven and exhibited no clinical decline or mortality. None of these adverse effects were seen in animals receiving either 8 {micro}L/g of MCTs PO or 8 {micro}L/g of saline IP. These findings suggest repeated IP administration of MCTs may cause dose-dependent toxicity, and mortality at high doses, but confers no adverse effects when administered via the PO route. SIGNIFICANCE STATEMENTMedium chain triglycerides (MCTs) are commonly used as an excipient in pharmacological studies involving laboratory animals. Our work provides much needed safety information regarding adverse effects of repeated MCTs administration via the intraperitoneal, but not the oral, route in mice.

pharmacology and toxicology↗

bioRxiv2024

Alzheimer's disease-associated genotypes differentially influence chronic evoked seizure outcomes and antiseizure medicine activity in aged mice

Structured AbstractO_ST_ABSINTRODUCTIONC_ST_ABSAlzheimers disease (AD) patients are at greater risk of focal seizures than similarly aged adults; these seizures, left untreated, may worsen functional decline. Older people with epilepsy generally respond well to antiseizure medications (ASMs). However, whether specific ASMs can differentially control seizures in AD is unknown. The corneal kindled mouse model of acquired chronic secondarily generalized focal seizures allows for precisely timed drug administration studies to quantify the efficacy and tolerability of ASMs in an AD-associated genetic model. We hypothesized that mechanistically distinct ASMs would exert differential anticonvulsant activity and tolerability in aged AD mice (8-15 months) to define whether rational ASM selection may benefit specific AD genotypes. METHODSAged male and female PSEN2-N141I versus age-matched non-transgenic control (PSEN2 control) C57Bl/6J mice, and APPswe/PS1dE9 versus transgene negative (APP control) littermates underwent corneal kindling to quantify latency to fully kindled criterion. Dose-related ASM efficacy was then compared in each AD model versus matched control over 1-2 months using ASMs commonly prescribed in older adults with epilepsy: valproic acid, levetiracetam, lamotrigine, phenobarbital, and gabapentin. RESULTSSex and AD genotype differentially impacted seizure susceptibility. Male PSEN2-N141I mice required more stimulations to attain kindling criterion (X2=5.521; p<0.05). Male APP/PS1 mice did not differ in kindling rate versus APP control mice, but they did have more severe seizures. There were significant ASM class-specific differences in acute seizure control and dose-related tolerability. APP/PS1 mice were more sensitive than APP controls to valproic acid, levetiracetam, and gabapentin. PSEN2-N141I mice were more sensitive than PSEN2 controls to valproic acid and lamotrigine. DISCUSSIONAD genotypes may differentially impact ASMs activity and tolerability in vivo with advanced biological age. These findings highlight the heterogeneity of seizure risk in AD and suggest that precisely selected ASMs may beneficially control seizures in AD, thus reducing functional decline.

neuroscience↗

bioRxiv2023

Diet composition and sterilization modifies intestinal microbiome diversity and burden of Theiler's virus infection-induced acute seizures

ObjectiveCentral nervous system infection with Theilers murine encephalomyelitis virus (TMEV) in C57BL/6J mice can model acquired epileptogenesis. Diet alters the acute seizure incidence in TMEV-infected mice; yet it is unclear whether intestinal dysbiosis may also impact acute or chronic behavioral comorbidities. This study thus assessed the impact of diet sterilization in a specific pathogen-free vivarium on acute seizure presentation, the composition of the gut microbiome, and chronic behavioral comorbidities of epilepsy. MethodsBaseline fecal samples were collected from male C57BL/6J mice (4-5 weeks-old; Jackson Labs) upon arrival. Mice were randomized to either autoclaved (AC) or irradiated (IR) diet (Prolab RMH 3000 - UU diets) or IR (Picolab 5053 - UW IR diet). Mice then underwent intracerebral TMEV or PBS injection three days later. Fecal samples were collected from a subset of mice at infection (Day 0) and Day 7 post-infection. Epilepsy-related working memory deficits and seizure threshold were assessed 6 weeks post-infection. Gut microbiome diversity was determined by 16S rRNA amplicon sequencing of fecal samples. ResultsTMEV-infected mice displayed acute handling-induced seizures, regardless of diet: 28/57 UW IR (49.1%), 30/41 UU IR (73.2%), and 47/77 UU AC (61%) mice displayed seizures. The number of observed seizures significantly differed: UW IR mice had 2.2{+/-}2.8 seizures (mean{+/-}standard deviation), UU IR mice had 3.5{+/-}2.9 seizures, and UU AC mice had 4.4{+/-}3.8 seizures during the 7-day monitoring period. The composition of the gut microbiome significantly differed in TMEV-infected mice fed the UU AC diet, with most measured differences occurring in Gram-positive bacteria. TMEV-infected mice fed the UU AC diet displayed worsened chronic working memory. SignificanceIntestinal dysbiosis evokes stark differences in acute seizure presentation in the TMEV model and vastly influences the trajectory of post-TMEV infection-induced behavioral comorbidities of epilepsy. Our study reveals a novel disease-modifying contribution of intestinal bacterial species after TMEV-induced acute seizures.

neuroscience↗

bioRxiv2021

Chronic Seizures Worsen Cognitive Function with Loss of Presenilin 2 Function in a Sex-Related Manner

Patients with early-onset Alzheimers disease (EOAD) are at elevated risk for seizures, including patients with presenilin 2 (PSEN2) variants. Like people with epilepsy, uncontrolled seizures may worsen cognitive function in AD. While the relationship between seizures and amyloid beta accumulation has been more thoroughly investigated, the role of other drivers of seizure susceptibility in EOAD remain relatively understudied. We therefore sought to define the impact of loss of normal PSEN2 function and chronic seizures on cognitive function in the aged brain. Male and female PSEN2 KO and age- and sex-matched wild-type (WT) mice were sham or corneal kindled beginning at 6-months-old. Kindled and sham-kindled mice were then challenged up to 6 weeks later in a battery of cognitive tests: non-habituated open field (OF), T-maze spontaneous alternation (TM), and Barnes maze (BM), followed by immunohistochemistry for markers of neuroinflammation and neuroplasticity. PSEN2 KO mice required significantly more stimulations to kindle (males: p<0.02; females: p<0.02) versus WT. Across a range of behavioral tests, the cognitive performance of kindled female PSEN2 KO mice was most significantly impaired versus age-matched WT females. Male BM performance was generally worsened by seizures (p=0.038), but loss of PSEN2 function did not itself worsen cognitive performance. Conversely, kindled PSEN2 KO females made the most BM errors (p=0.007). Chronic seizures also significantly altered expression of hippocampal neuroinflammation and neuroplasticity markers in a sex-specific manner. Chronic seizures may thus significantly worsen hippocampus-dependent cognitive deficits in aged female, but not male, PSEN2 KO mice. Our work suggests that untreated focal seizures may worsen cognitive burden with loss of normal PSEN2 function in a sex-related manner.

neuroscience↗

bioRxiv2021

Continuous Seizure Emergency Evoked in Mice with Pharmacological, Electrographic, and Pathological Features Distinct from Status Epilepticus

ObjectivesBenzodiazepines are the standard of care for the management of sustained seizure emergencies, including status epilepticus (SE) and seizure clusters. Seizure clusters are a variably defined seizure emergency wherein a patient has multiple seizures above a baseline rate, with intervening periods of recovery, distinguishing clusters from SE. While phenotypically distinct, the precise pathophysiological and mechanistic differences between SE and seizure clusters are under studied. Preclinical interrogation is needed to help uncover the behavioral, physiological, and pathological mechanisms associated with seizure emergencies in order to better manage these events in the susceptible individual. MethodsHerein, we characterize a novel model of sustained seizure emergency induced in CF-1 mice through the combined administration of high-dose phenytoin (PHT; 50 mg/kg, i.p.) and pentylenetetrazol (PTZ; 100 mg/kg, s.c.). ResultsIn the present manuscript we describe a mouse model of sustained seizure emergency that is physiologically, pharmacologically, and histologically distinct from SE. Acute administration of PHT 1 hour prior to s.c.PTZ led to significantly more mice with continuous seizure activity (CSA; 73.4%) versus vehicle-pretreated mice (13.8%; p<0.0001). CSA was sensitive to lorazepam and valproic acid when administered at seizure onset, as well as 30-minutes post-seizure onset. Carbamazepine worsened seizure control and post-CSA survival. Mice in CSA exhibited EEG patterns distinct from kainic acid-induced SE and s.c.PTZ alone, clearly differentiating CSA from SE and s.c.PTZ-induced myoclonic seizures. Neuropathological assessment by FluoroJade-C staining of brains collected 24-hours later revealed no neurodegeneration in any mice with CSA, whereas there was widespread neuronal death in brains from KA-SE mice. SignificanceThis study defines a novel mouse model on which to elucidate the mechanistic differences between sustained seizure emergencies (i.e. SE and seizure clusters) to improve discovery of effective clinical interventions and define mechanisms of seizure termination. Key Points BoxO_LISeizure clusters are a variably defined seizure emergency that is sensitive to benzodiazepines, distinct from status epilepticus. C_LIO_LIThe mechanistic differences between seizure clusters and status epilepticus are not well defined. C_LIO_LIWe report a mouse seizure emergency model that is phenotypically, pathologically, and pharmacologically distinct from status epilepticus. C_LIO_LIThis mouse model provides a novel platform on which to further interrogate the mechanisms underlying seizure emergencies. C_LI

neuroscience↗

bioRxiv2020

Development of an Antiepileptogenesis Drug Screening Platform: Effects of Everolimus and Phenobarbital

ObjectiveThe kainic acid (KA)-induced status epilepticus (SE) model in rats is an etiologically-relevant animal model of epileptogenesis. Just as in patients, who develop temporal lobe epilepsy (TLE) following SE, this rat model of KA-induced SE very closely recapitulates many of the clinical and pathological characteristics of human TLE that arise following SE or another neurological insult. Spontaneous recurrent seizures (SRS) in TLE can present after a latent period following a neurological insult (TBI, SE event, viral infection, etc.). Moreover, this rat model of TLE is ideally suited for preclinical studies to evaluate the long-term process of epileptogenesis and screen putative disease-modifying/antiepileptogenic agents. This report details the pharmacological characterization and methodological refinement of a moderate-throughput drug screening program using the post KA-induced SE model of epileptogenesis in male Sprague Dawley rats to identify potential agents that may prevent or modify the onset or severity of SRS. Specifically, we sought to demonstrate whether our protocol could prevent the development of SRS, or lead to a reduced frequency/severity of SRS. MethodsRats were administered everolimus (2-3 mg/kg, P.O. commencing at 1, 2, or 24-hrs after SE onset) or phenobarbital (60 mg/kg, beginning 1 hr after SE onset). The rats in all studies (n=12/treatment dose/study) were then followed intermittently by video-EEG monitoring; i.e., 2-weeks on/2-weeks off, 2-weeks on epochs to determine latency to onset of SRS, and disease burden following SRS onset. ResultsWhile there were no adverse side effects observed in any of our studies, no treatment conferred a significant disease modifying effect, nor did any agent prevent the presentation of SRS by 6 weeks post-SE onset. ConclusionsWhile neither phenobarbital nor everolimus administered at several time points post-SE onset prevented the development of SRS, we herein demonstrate a moderate-throughput screen for potential antiepileptogenic agents in an etiologically-relevant rodent model of TLE. Key PointsO_LIDisease-modifying therapies are needed to prevent or attenuate the burden of epilepsy in at-risk individuals. C_LIO_LIWe report a moderate-throughput screening protocol to identify disease-modifying agents in a rat post-kainic acid status epilepticus model. C_LIO_LIEverolimus was administered at multiple time points post-status epilepticus with no effect on spontaneous seizures up to 6 weeks later. C_LIO_LIRepeated administration of phenobarbital also did not prevent the development of spontaneous recurrent seizures up to 6 weeks post SE. C_LIO_LIWhile we did not identify any effect of either agent, our approach provides a moderate-throughput screen for antiepileptogenesis. C_LI

neuroscience↗