Characterizing Network Inhibition and Cognitive Deficit in Kcnt1 Mice
Rachimi, Eli
Rachimi, Eli
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Abstract
Mutations to the Kcnt1 gene have been implicated in a range of developmental seizure disorders with high rates of intellectual disability. We hypothesize that Kcnt1 mutations preferentially affect somatostatin positive (SST+) interneurons, which regulate the firing of excitatory neurons in the hippocampal dentate gyrus, by making them hypoexcitable. This leads to the disinhibition of local circuits underlying the coordination of intercortical and corticohippocampal networks. Disinhibited networks, as a result of hypoexcitable interneurons, result in generalized seizures and learning and memory deficits. To address this hypothesis, we used several approaches in heterozygous and homozygous Kcnt1-YH and wild-type mice to interrogate corticohippocampal networks on the CA1 and dentate gyrus somatodendritic axes: 1) Behavior through active avoidance on a rotating arena; 2) in vivo electrophysiology measurements of the hippocampus using high density laminar silicon probes; and 3) SST+ interneuron specific optogenetics. Our data suggest that Kcnt1 mice demonstrate cognitive deficit phenotypes on the active avoidance task in which severity correlates with genotype. Likewise, we have found a relationship between genotype and the degree of the perturbation to corticohippocampal circuits, where Kcnt1 mice exhibit interictal epileptiform discharges. Preliminary results from optogenetic stimulation of SST+ interneurons responsible for regulating these inputs has shown that we can limit this circuit dysfunction and significantly decrease interictal discharge rate.
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Date
1/1/2026
Student Status
Senior (Graduating in 2026)
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Poster
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Biochemistry
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College of Arts and Sciences
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Life Science