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Synaptic Integration in CA1 Pyramidal Neurons Is Intact despite Deficits in GABAergic Transmission in the Scn1a Haploinsufficiency Mouse Model of Dravet Syndrome

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Abstract Mutations of SCN1A, which encodes the voltage-gated sodium channel Nav1.1, can cause epilepsy disorders such as Dravet syndrome (DS) that are comorbid with wide-ranging neurologic dysfunction. Many studies suggest… Click to show full abstract

Abstract Mutations of SCN1A, which encodes the voltage-gated sodium channel Nav1.1, can cause epilepsy disorders such as Dravet syndrome (DS) that are comorbid with wide-ranging neurologic dysfunction. Many studies suggest that Nav1.1 haploinsufficiency causes forebrain GABAergic interneuron hypoexcitability, while pyramidal neuron physiology is mostly unaltered, and that this serves as a primary cell physiology phenotype linking mutation to disease. We hypothesized that deficits in inhibition would alter synaptic integration during activation of the hippocampal microcircuit, thus disrupting cellular information processing and leading to seizures and cognitive deficits. We tested this hypothesis using ex vivo whole-cell recordings from CA1 pyramidal neurons in a heterozygous Scn1a knock-out mouse model and wild-type (WT) littermates, measuring responses to single and patterned synaptic stimulation and spontaneous synaptic activity. Overall, our experiments reveal a surprising normalcy of excitatory and inhibitory synaptic temporal integration in the hippocampus of Scn1a haploinsufficient mice. While miniature IPSCs and feedforward inhibition and were decreased, we did not identify a pattern or frequency of input that caused a failure of synaptic inhibition. We further show that reduced GABA release probability and subsequent reduced short-term depression may act to overcome deficits in inhibition normalizing input/output functions in the Scn1a haploinsufficient hippocampus. These experiments show that CA1 pyramidal neuron synaptic processing is surprisingly robust, even during decreased interneuron function, and more complex circuit activity is likely required to reveal altered function in the hippocampal microcircuit.

Keywords: pyramidal neurons; ca1 pyramidal; synaptic integration; physiology; dravet syndrome

Journal Title: eNeuro
Year Published: 2022

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