Neurophysiological mechanisms of oxytocinergic signaling in the dentate gyrus

About This Grant

PROJECT SUMMARY Social memory is a critical process for learning to navigate the world, and deficits in social processing are common in neuropsychiatric disorders like autism, and Fragile X syndrome (FX). Current treatments for these disorders often fail to effectively address these social deficits, highlighting the need for a deeper understanding of the underlying mechanisms. A shared characteristic among these disorders is dysfunction of the hippocampus, a brain region recently linked to social memory. Hippocampal area CA2 and signaling of the social neuropeptide oxytocin within CA2 play a known role in social memory. However, research on the specific role of the dentate gyrus, a hippocampal region that sends direct excitatory input to CA2, during social memory processing, including oxytocin signaling, is lacking. The goal of this project is to identify how oxytocin signaling within the dentate gyrus contributes to social memory processing. My preliminary data shows that oxytocin increases the excitability and enhances synaptic transmission of dentate granule cells in wild type mice, while granule cell excitability may be impaired in a mouse model of Fragile X syndrome (FX mice). This project will use in vitro electrophysiology to record from dentate granule cells in response to oxytocin in wildtype mice and FX mice. Specific Aim 1 will identify potassium channels modulated by oxytocin in dentate granule cells. This aim will test the hypothesis that oxytocin modulates KV1 voltage-gated and KIR potassium channels. Preliminary data suggest that oxytocin enhances synaptic transmission from the entorhinal cortex to dentate granule cells, however, the locus and mechanism of this effect is not known. Specific Aim 2 will investigate how oxytocin modulates synaptic transmission in the dentate gyrus. Preliminary recordings from FX dentate granule cells found reduced excitability compared to wild type. Specific Aim 3 will determine the cellular mechanisms underlying this lower excitability and investigate if granule cell responses to oxytocin are impaired in FX mice. The results from this project will provide insight into the mechanisms behind oxytocin’s modulation of the dentate gyrus and may inform future treatments for prevalent social deficits. The findings anticipated from these proposed experiments will be the initial evidence of oxytocin’s modulation of KV1 in dentate granule cells, and the first indication that oxytocin modulates synaptic transmission to the granule cell layer, which may play a crucial role in social cognition. This fellowship will allow me to learn a wide array of in vitro electrophysiological and microscopy techniques, practice disseminating my research at national conferences, and acquire skills in mentoring and teaching undergraduate students. Through this fellowship I aim to develop not only essential technical skills, but also conceptual and professional competencies necessary for establishing a career as an independent researcher at an R1 institution.