Fig. 7. Summary of sex-specific impacts of gephyrin phosphorylation: postnatal development and adult impact on PV neurons and hippocampal function.

Postnatal development: In WT mice, gephyrin phosphorylation levels decline during the first two postnatal weeks in males and females. This phosphorylation impacts gephyrin’s influence on normal sexually dimorphic development (e.g., via post-synaptic regulation of GABAergic signaling, or regulation of gephyrin’s non-synaptic functions) to establish sexual dimorphism in putative PV neuron (1) transcriptional state, (2) density within the stratum pyramidale, and (3) electrophysiological properties and input. However, blocking this developmental phosphorylation in Gphn^S268A/S270A mice prevents the development of these sex differences. Adult impacts: Sex differences in PV neuron density that emerge postnatally are preserved in adult WT mice, where PV neuron electrophysiological function and inputs are different between males and females. Despite these PV neuron sex differences, hippocampal function is convergent. In Gphn^S268A/S270A mice, PV neuron sex differences are blocked and associated with disrupted hippocampal cognition in males (contextual memory) and females (object memory). Taken together, gephyrin phosphorylation establishes sex differences in PV neuron development and adult function, disruption of which leads to sex-specific deficits in cognition.