Hippocampal Circuit Dysfunction in SCN8A Gain-of-Function Encephalopathy

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PROJECT SUMMARY / ABSTRACT Developmental epileptic encephalopathy (DEE) is a complex disorder characterized by refractory seizures, developmental delay, cognitive disabilities, movement disorders and elevated risk of sudden unexpected death (SUDEP) (1-4). De novo missense mutations in the sodium channel gene SCN8A have been identified in more than 300 patients with DEE, resulting in the disorder early infantile epileptic encephalopathy 13 (EIEE13; OMIM #614558) or SCN8A encephalopathy (3). We have reported that the most common pathogenic mechanism of SCN8A encephalopathy is gain-of-function (GOF) changes in sodium channel Nav1.6. We developed a mouse model with expression of the patient mutation p.Arg1872Trp (R1872W) that is dependent on Cre-induced recombination (5). This model allows seizures to be induced in a controlled fashion in the adult animal, bypassing the early lethality of constitutively expressed mutations. By crossing conditional R1872W mice with CAG-Cre-ER mice expressing a tamoxifen-inducible Cre transgene, we can induce spontaneous seizures in adult mice that recapitulate patient phenotypes. The identical genetic background of these congenic mice contributes to experimental reproducibility. Hippocampal ripples are fast oscillations seen during non-REM (NREM) sleep and quiet wakefulness. Behavioral activity patterns, such as the sequential firing of hippocampal place cells during navigation, are replayed in a compressed neural sequence during ripples, helping to consolidate related memories. Ripples are impaired in a multitude of epilepsies, likely contributing to memory and cognitive deficits in patients. While healthy and pathological ripple dynamics are well studied in temporal lobe epilepsy and more recently in a global SCN1A haploinsufficiency model, there is a gap in knowledge regarding the impact on ripples of SCN8A encephalopathies. It is therefore important to investigate the effects of SCN8A encephalopathy on ripples and other hippocampal circuit output. Our central hypothesis is that both ripples (Aim 1) and hippocampal place cell firing (Aim 2) are progressively impaired during the development of SCN8A encephalopathy. The rationale for this hypothesis comes from our published observations that patient mutations cause elevated activity of Nav1.6 channels due to premature activation or impaired inactivation, resulting in hyperactivity of cultured hippocampal pyramidal cells. The completion of these Aims will result in the collection of massive datasets that will be shared with the epilepsy community, allowing for community-wide dissection of seizure and interictal dynamics, seizure- onset and SUDEP prediction algorithms, as well as changes in sleep-wake rhythms over time. The observed changes in hippocampal circuit dynamics will generate further hypotheses that can be dissected using cell type- and region-specific CRE transgenes in a follow-up R01 application.