THE ROLE OF MENA IN STRUCTURAL AND MOLECULAR ORGANIZATION OF CORTICAL INHIBITORY SYNAPSES

Neurons have adapted various mechanisms that enable semi-autonomous regulation of protein homeostasis in their distal compartments, like synapses, in order to maintain their structural and functional polarity, and to rapidly respond to their microenvironment. However, the way synaptic diversity emerges from dynamic modulation of subcellular molecular components and protein turnover, remains elusive. Previous work from our lab on developing neurons, has identified a dual role of the protein Mena in the regulation of local translation (LT) in axons, and in actin cytoskeleton remodeling. Both processes are crucial for synapse formation and activity, but the exact mechanism of Mena function and its potential role beyond development remain elusive. In this study, we report a) the preferential localization of Mena in pre- and postsynaptic sides of inhibitory synapses, and b) its synaptic interaction with specific cell-adhesion molecules, regulators of local translation and novel organizers of inhibitory synapses. Concomitantly, we observe significant synaptic defects in mice with genetic ablation of Mena (Mena KO), including hindered formation of inhibitory synapses (ex-vivo), hastened formation of perineuronal nets, changes in size of presynaptic boutons around PV interneurons (in-vivo), reduced availability of important synaptic proteins like VAMP2, and behavioral alterations. Based on our findings, we propose that Mena functions in synapses by coordinating actin dynamics and LT, to shape the local proteome and cytoskeleton. Our work thus far, uncovers novel mechanistic insights into synapse diversification, and contributes to our understanding of cortical inhibitory circuit formation and activity, which is often impacted in several neurodevelopmental disorders.