The molecular basis of synaptic specificity

University Of California Los Angeles, Los Angeles CA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT The long-term objective of our studies is to understand the molecular mechanisms underlying the formation of synaptic connections between neurons in the brain. These patterns are complex and highly specific and they represent the genetic hardwiring of behavior. Extensive maps of connections between neurons have been assembled in Drosophila melanogaster. These maps of unprecedented completeness provide an extraordinary opportunity to leverage the molecular and genetic toolkit in Drosophila and the dramatic advances in light microscopy to uncover the logic and mechanistic basis for the formation of the connectome. Here we focus on the development of specific patterns of connections in the Drosophila visual system. We focus on how different synapses form in different domains of the same dendrite and how neurons select between different potential synaptic partners. Specific proteins will be tagged in cell-type specific ways allowing for precise subcellular resolution of protein distribution. The precise localization of proteins to specific synapses is facilitated by imaging isotropically expanded tissue using light-sheet microscopy. Synapse associated proteins are identified in complexes associated with tagged neurotransmitter receptors using an affinity purification-mass spectrometry workflow. This proposal seeks to close the gap between cell recognition molecules mediating interactions between developing axons and dendrites and the precise patterns of synapses between neurons. We explore this relationship by focusing on cell recognition molecules which allow developing processes of different axons and dendrites to discriminate between one another and protein complexes comprising different neurotransmitter receptor subunits and associated proteins at synapses within specific dendritic spatial domains. The specific aims of this project are: 1. Uncovering the molecular basis of synaptic specificity at GluClα synapses in the distal domain of T4 dendrites. These studies will focus on Mmd, a fly homolog of a mammalian synaptic adhesion molecule Adam22 and other GluClα-associated proteins; 2. Uncovering the molecular basis of synaptic specificity at nAChRα5-containing synapses in the central domain of T4 dendrites. These studies will focus on Side-VI protein, a synapse-specificity related protein, and other AChRα5-associated proteins; and 3. Uncovering the molecular basis of synaptic specificity at Rdl-containing synapses in the proximal domain of T4 dendrites. These studies will focus on the role of the Turtle (Tutl) protein, a fly homolog of mammalian Igsf9b, a synaptic adhesion protein selective for GABAergic synapses. It will also explore other proteins associated with Rdl. These studies will provide fundamental insights into the molecular logic and mechanisms regulating the formation of connections between neurons. As disruption of connectivity plays a central role in neurological and psychiatric disorders these studies provide a basis for the development of effective therapies in the future.