Abstracts

Rationale:
In patients with epileptic encephalopathy (EE), severe cognitive and behavioral dysfunction is thought to be principally mediated by pervasive and often intractable seizures. Several genetic etiologies of EE have been identified, including homozygous mutations in KCNA1, which encodes a ubiquitously expressed voltage gated potassium channel subunit. Prior attempts at demonstrating features of “encephalopathy” in such EE models have employed task-based assays of spatial learning or exploration, which are brief unidimensional assessments that are often confounded by human exposure and unconscious bias. In this study, we applied instrumented home-cage monitoring and wireless EEG to noninvasively visualize perturbations in higher-order patterns of spontaneous murine behavior that may represent more ethologically sound correlates of encephalopathy.
Method:
6-8 week old WT (27) and KCNA1 KO (22) littermates were assessed in instrumented home-cage chambers (Noldus Phenotypers) for 48-72h, designed to simultaneously tally movement, sheltering, feeding, licking and behaviorally defined sleep. A separate group of KO mice (n=5) were similarly assessed in these chambers with simultaneous wireless EEG recordings (EMKA Technologies).
Results:
As described by Tecott (2008 PNAS), WT mice oscillated between two discrete behaviorally defined states: active (patrolling, foraging) and inactive (sleep, quiet wakefulness). KO mice displayed significantly more active states that were morphologically longer in duration and which accumulated greater distances. When examined with simultaneous EEG recordings, spontaneous seizures predominantly emerged from active states. Valproic acid treatment improved seizure frequency and active state durations without affecting the mean number of daily active states.  
Conclusion:
Our results reveal that an ion channel, designed to regulate neuronal excitability at millisecond timescales, pleiotropically modulates fundamental higher-order features of behavioral organization. We hypothesize that disrupted active state structure in Kcna1 KO mice is a correlate of an encephalopathic state, with distinct epileptic (anticonvulsant-remediable) and underlying static/lesional (non-remediable) components. Ongoing experiments seek to employ a genetic approach to understanding the developmental contributions of Kcna1 loss, and how KCNA1-associated proteins (including LGI1, CNTNAP2, STARGAZIN) modulate active state morphology.  
Funding:
:VK receives support from the NIH (1K08NS110924-01), an AES Junior Investigator Award (2020), SK Life Science, and seed funding from Baylor College of Medicine’s Office of Research.