Characterization of the role of LRRTMs in synaptic plasticity and memory formation
Project Overview
The key neuropathology underlying ASDs is abnormal neuronal communication as a result of altered synapse formation, function and plasticity. Specialized synaptic proteins known as cell adhesion molecules (CAMs) critically regulate synapse formation during brain development. CAMs known as Leucine Rich-Repeat TransMembrane neuronal proteins (LRRTMs), have recently been identified in screens for novel synapse promoting molecules. LRRTMs are highly synaptogenic, are located postsynaptically on glutamatergic synapses, and interact with presynaptic neurexins (Siddiqui et al., 2011). To date, Neurexin genes are the most strongly linked gene variants associated with ASDs (Sudhof et al., 2008). Given that multiple LRRTMs and neurexin gene variants are implicated in autism and intellectual disability and the lack of effective treatments for these disorders, it is crucially important that we understand the roles of LRRTMs in nervous system function. We generated LRRTM1 and LRRTM2 double knockout (DKO) mice models with the overall goal of determining how LRRTMs regulate synaptic transmission, plasticity and cognitive function. This project is highly novel as no constitutive model of dual LRRTM1/2 KO has yet been tested to determine if LRRTMs modulate synaptic function or memory. Due to the high expression profile of LRRTM1/2 (Lauren et al., 2003) and its role in memory formation, all experiments will be conducted in mouse hippocampus, subregion CA1. The following fundamental questions will be addressed using the DKO model: 1) What are the effects of LRRTM1/2 DKO on synaptic physiology and plasticity in the hippocampus 2) Do LRRTMs play a role in mediating synaptic organization and morphology? 3) Are synaptic proteomic profiles changed in the absence of LRRTM1/2? 4) Is memory performance altered in LRRTM1/2 DKOs?
Principal Investigator
Steven Connor , University of British Columbia
Partners and Donors
Bell Canada