The role of Shank3 in the wiring of VIP interneurons in the mouse visual cortex

Abstract

The cerebral cortex ability to control sensory processing and cognitive function relies on an intricate network of highly interconnected excitatory pyramidal neurons and inhibitory interneurons. While Vasoactive intestinal polypeptide (VIP)-expressing interneurons only represent a small fraction of cortical neurons, their unique connectivity and essential role in the fine tuning of local microcircuits and in controlling local pyramidal cell activity have recently make them the focus of extensive research. The postsynaptic protein Shank3, is a master scaffolding protein in excitatory synapses and recent transcriptomic studies have suggested that it is enriched in cortical VIP interneurons. However, the precise pattern of expression of Shank3 and its role in the wiring of VIP interneurons during postnatal development are yet to be established. Here we investigated whether Shank3 is a key component of the rich excitatory synaptic connectivity that VIP interneurons receive. Using in situ hybridisation and immunohistochemistry throughout mouse postnatal development, we first show that Shank3 is enriched in VIP interneurons compared to other interneurons classes, namely Parvalbumin (PV) interneurons, both at the protein and the RNA level. We find that its expression is particularly abundant in VIP interneurons during the visual cortex ocular dominance critical period where it can be found in the postsynaptic density of excitatory inputs onto the soma, dendritic shaft, and dendritic spines of VIP cells. Despite higher Shank3 levels at this age, we found that VIP interneurons receive similar densities of Shank3+ shaft and somatic synapses to PV interneurons. Moreover, by conditionally deleting Shank3 specifically from VIP interneurons we uncover that Shank3 is not necessary for the establishment of excitatory inputs into these cells in either of these cellular compartments. Nonetheless, our preliminary results suggest that, in the mature visual cortex, Shank3 may function as a regulator of spine dynamics in cortical VIP interneurons, controlling the stabilisation of “winning” synaptic contacts onto these cells. All in all, our findings highlight a potential novel mechanism whereby VIP interneuron inputs are dynamically and specifically integrated.

Date of Award	1 Oct 2024
Original language	English
Awarding Institution	King's College London
Supervisor	Beatriz Rico (Supervisor) & Adil Khan (Supervisor)