Molecular mechanisms of synapse development and specificity

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Highly specific patterns of connectivity among nerve cells is a fundamental principle of brain organization and function. The development of these specialized connections known as synapses involves a series of distinct processes including targeting of axons to defined zones or laminae, recognition and engagement with molecular targets on select dendritic regions of specific cell-types, pre- and post-synaptic differentiation and maturation of synapses with characteristic molecular identities and functional properties. A class of adhesion proteins known as synapse organizing proteins mediates multiple steps of synapse development. Whereas their roles in synapse formation have been well studied, their contribution to synaptic specificity is less well explored. Under this proposed research program, my HQP, 1 Ph.D. student and 2 M.Sc. students, and I will address how leucine-rich repeat transmembrane neuronal (LRRTM) family of synapse organizers contributes to synaptic specificity. The LRRTMs are expressed in discrete cell populations and dendritic laminae and thus are ideally suited for mediating lamina specific synapse development. Our first objective is to determine the contributions of LRRTM1 and LRRTM2 to lamina selective synapse development in the hippocampus. Our second objective is to dissect the molecular mechanism through which LRRTMs mediate synapse development. Finally, through in vivo manipulation, we propose to test whether synapse organizing proteins functioning through alternate pathways may restore defects in synaptic circuitry in mice lacking LRRTMs from birth. We expect that LRRTM1 and LRRTM2 are important for selective synapse development in hippocampal CA1 stratum radiatum and stratum lacunosum moleculare respectively and that they need to engage both presynaptic and postsynaptic binding partners to mediate bidirectional synapse development. Whereas lamination is a central organizing principle of both vertebrate and invertebrate brains, recent large scale screening projects point to the selective expression of adhesion proteins in defined cell populations and brain regions. Although this proposal will directly address the origins of synaptic specificity in the entorhinal cortex-CA1 and the CA3 Schaffer Collateral –CA1 synaptic pathways, the outcomes are expected to be representative of neural circuit formation generally and will thus be of great interest to the wider neuroscience community.