“Gephyrin phosphorylation drives sex-dimorphic GABAergic connectivity in the hippocampus”
Shiva Tyagarajan, PhD
Neurodevelopmental Pharmacology Lab
Institute of Pharmacology and Toxicology
University of Zurich, Switzerland

Abstract: Fast GABAergic synaptic transmission in the central nervous system is enacted via the pre-synaptic output of inhibitory interneurons and the post-synaptic activation of GABAA receptors (GABAARs) which in turn are organised by the scaffolding protein gephyrin. Gephyrin is the substrate for a plethora of post-translational modifications which affects its own clustering at postsynaptic sites and facilitates interactions with its partner proteins. Here, we provide evidence for differential gephyrin phosphorylation between males and females in the hippocampus during development. By developing a mutant mouse model in which serines 268 and 270 are mutated to alanines to constitutively prevent phosphorylation we examined how differential gephyrin phosphorylation between the sexes contributes to hippocampal GABAergic connectivity. Characterisation of behavioural phenotypes in these mutant mice has revealed deficits in learning only in the female mice, with altered inhibitory connectivity in the hippocampal CA1 formation leading to functional changes in inhibitory synaptic input. This sexually dimorphic GABAergic phenotype is facilitated by alteration in PV interneuron number. Using a combination of morphological, functional and PV neuron specific patch-seq analysis, we uncover an unexpected involvement of gephyrin phosphorylation in controlling PV interneuron survival and connectivity during development by activating transcriptional program in a sex-specific manner..

Tuesday, July 26, 2022 at 12:00 pm

Free and open to the public. Email Conte@Harvard.edu for zoom info