Abstracts

Rationale: Autism and epilepsy are common childhood neurological disorders with significant heterogeneity of clinical phenotypes as well as risk factors. There is a high co-morbidity of autism and epilepsy but the molecular underpinnings of this overlap are unclear. The neuropathology of autism and epilepsy has distinctly similar histology implicating the processes of neurogenesis, neural migration, programmed cell death, and neurite outgrowth. Genetic advances have identified multiple molecules that participate in neural development, brain network connectivity, and synaptic function which could be involved in the pathogenesis of autism including the guidance system Semaphorin 3F-Neuropilin 2 signaling. Cell specific ablation of Sema 3F and NPN2 genes lead to defects in cortical and hippocampal interneuron circuitry and spontaneous seizures. However the cell specific basis of the epilepsy, epileptiform activity (IEDs), and behavior/cognition have not been explored in the absence of Sema 3F-NPN2 signaling. Methods: Videotaping, automated home cage analyses, and open field analyses were performed in CKO mice with interneuron and principal neuron cell specific ablation of the Sema 3F gene.Results: Videotaping of Sema 3F CKO mice reveals that behavioral seizures are only noted in mice with interneuron specific deletion of Sema 3F (p<0.0001). Home cage analyses and open field testing suggest deletion of Sema 3F signaling leads to altered sleep rhythms (p<0.02), increased repetitive behaviors (grooming, p<0.04), and reduced non-selective attention (rearing episodes, p<0.05). On going experiments will correlate epileptiform activity, GABAergic circuitry, and cognition/behavior in the same mice.Conclusions: In summary, the seizure prone CKO mice of the Sema 3F-NPN2 signaling system recapitulate some aspects of human autism epilepsy patients. Further studies of mouse models of autism and epilepsy should identify therapeutic drug targets to ameliorate the burden of neurologic disease in these children.