Abstracts

Rationale: Mood and anxiety disorders are among the most important psychiatric comorbidities of epilepsy. In temporal lobe epilepsy, comorbid major depressive disorder is underdiagnosed and associated with seizure pharmacoresistance and elevated suicide rates. The neuroanatomical and molecular substrates underlying this comorbidity remain poorly understood. Human heterozygous mutations in KCNA1 are associated with temporal lobe epilepsy. Mice with homozygous deletions of Kcna1 display spontaneous seizures of hippocampal onset and limbic semiology, constituting a genetically valid model of temporal lobe epilepsy. Whether these mice display features of interictal depression/"dysphoric" disorder has never been explored. Methods: At 7 weeks of age, wild type (WT), heterozygous (Kcna1^+/-) and homozygous (Kcna1^-/-) mice (n=7-8) were individually housed in instrumented home cages fitted with a ceiling-mounted infrared video camera designed to permit live video tracking at a sampling rate of 15 Hz.  These cages were also furnished with an infrared lucent shelter, two lickometered water sources (0.8% sucrose Vs drinking water alone) and a “beam-break” mouse feeding meter. We examined multiple simultaneously measured behavioral variables during “baseline recordings” (lasting 48-72h long) and during specific “provocative maneuvers” (e.g., timed bright light stimuli, pentylenetetrazole injections). Sociability/social contact was also studied in a subgroup of female mice who were exposed to an unfamiliar female mouse during a timed home cage social interaction trial. Results: Compared to WT mice, Kcna1^+/- displayed mild psychomotor retardation and anhedonia (p<0.05). This was concurrent with their lowered seizure threshold, determined by their overall response to a home cage chemoconvulsant challenge. In contrast, Kcna1^-/- mice displayed anhedonia in concert with pronounced hyperactivity, together with impairments in sociability (p<0.05). Neither Kcna1^+/- nor Kcna1^-/- mice displayed changes in anxiety-like behavior assayed within the home cage. Conclusions: These results demonstrate that with prolonged home cage monitoring, we observe the presence of a mild depression-like phenotype in Kcna1^+/- mice concurrent with their elevated seizure risk. Kcna1^-/- mice display pronounced hyperactivity with anhedonia reflective of a putative comorbid mood disorder that resembles atypical depression in humans. We are currently examining the precise temporal relationships between seizure occurrence and interictal changes in emotionality in Kcna1^-/- mice using simultaneous wireless EEG. Funding: Baylor College of Medicine Seed Grant (VK), American Academy of Neurology Clinical Research Training Fellowship in Epilepsy (VK)