PT  - JOURNAL ARTICLE
AU  - Chancey, Jessica Hotard
AU  - Howard, MacKenzie Allen
TI  - Synaptic integration in CA1 pyramidal neurons is intact despite deficits in GABAergic transmission in the <em>Scn1a</em> haploinsufficiency mouse model of Dravet syndrome
AID  - 10.1523/ENEURO.0080-22.2022
DP  - 2022 May 05
TA  - eneuro
PG  - ENEURO.0080-22.2022
4099  - http://www.eneuro.org/content/early/2022/05/05/ENEURO.0080-22.2022.short
4100  - http://www.eneuro.org/content/early/2022/05/05/ENEURO.0080-22.2022.full
AB  - Mutations of SCN1A, which encodes the voltage-gated sodium channel Nav1.1, can cause epilepsy disorders such as Dravet syndrome that are comorbid with wide-ranging neurological 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 knockout mouse model and wild type 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.Significance statementMouse models of genetic epilepsy disorders are useful tools for better understanding the neurophysiology underlying the seizures and cognitive comorbidities of disease. Here, we use a Scn1a haploinsufficieny model of Dravet syndrome (DS) to investigate synaptic integration and input/output functions, which are fundamental forms of neuronal information processing. We found that while DS model hippocampal pyramidal neurons had modest deficits in inhibition, synaptic integration and input/output functions were surprisingly normal. We also found that changes in GABA release probability may be a compensatory mechanism by which the hippocampal circuit overcomes deficits in inhibition to normalize input/output functions.