Home-cage behavior in the Stargazer mutant mouse.

In many childhood-onset genetic epilepsies, seizures are accompanied by neurobehavioral impairments and motor disability. In the Stargazer mutant mouse, genetic disruptions of Cacng2 result in absence-like spike-wave seizures, cerebellar gait ataxia and vestibular dysfunction, which limit traditional approaches to behavioral phenotyping. Here, we combine videotracking and instrumented home-cage monitoring to resolve the neurobehavioral facets of the murine Stargazer syndrome. We find that despite their gait ataxia, stargazer mutants display horizontal hyperactivity and variable rates of repetitive circling behavior. While feeding rhythms, circadian or ultradian oscillations in activity are unchanged, mutants exhibit fragmented bouts of behaviorally defined "sleep", atypical licking dynamics and lowered sucrose preference. Mutants also display an attenuated response to visual and auditory home-cage perturbations, together with profound reductions in voluntary wheel-running. Our results reveal that the seizures and ataxia of Stargazer mutants occur in the context of a more pervasive behavioral syndrome with elements of encephalopathy, repetitive behavior and anhedonia. These findings expand our understanding of the function of Cacng2.

Spontaneous Recurrent Seizures Mediated Cardiac Dysfunction via mTOR Pathway Upregulation: A Putative Target for SUDEP Management.

BACKGROUND: Alteration in electrophysiology, leading to cardiac dysfunction and subsequently a nontraumatic death is a complication of epilepsy known as "SUDEP" (Sudden Unexpected Death in Epilepsy). AIMS: The present study was designed to understand the molecular changes and cardiac parameters during different phases of epileptogenesis in lithium-pilocarpine (Li-pilo) rat model of epilepsy. METHODS: The animals were exposed to Li-pilo to induce Spontaneous Recurrent Seizures (SRS). Noninvasive blood pressure and electrocardiography was recorded at 7th, 28th and 75th day following pilocarpine administration, considered as latent, initial and late SRS phases, respectively. The serum biochemistry, cardiac histopathology, protein and mRNA expressions were studied, following electrocardiography on day 75. RESULTS: The mean arterial pressure decreased during the latent phase, thereafter it progressively increased during the initial and the late SRS phases, as compared to the basal and the latent phase. Histopathological analysis of the heart sections indicated hypertrophy, degenerative changes and fibrous tissue deposition in epileptic animals, along with increased levels of lactate dehydrogenase and creatine kinase-MB in the serum. The expression of HIF-1α, phospho-S6, phospho-mTOR, TGF-ß, collagen I and Na+/K+-ATPase α1 proteins, and mRNA levels of HIF-1α, mTOR, Rps6, Scn1b, Scn3b, Nav1.5 and TGF-ß were increased in the cardiac tissue of epileptic animals, as compared to control. CONCLUSION: Our results conclusively showed that Li-pilo-induced SRS leads to cardiac dysfunction via mTOR pathway upregulation, thus suggested the regulatory control of mTOR pathway as a potential target for SUDEP management.