Grant: Discovery Grants Program - Individual

The development of accurate synaptic connections is a prerequisite for brain organization. Though synapse organizing proteins mediate synapse development ubiquitously, relatively little is known about the molecular factors governing the specificity of synapse development and function. The long-term objective of my NSERC research program is to discover the fundamental molecular and neural circuit mechanisms governing brain organization and function. Enabled by my NSERC DG, we made significant progress in uncovering essential rules of synapse organization and plasticity in the hippocampus, retina and mediodorsal thalamus. In the next five years, we will extend our studies to investigate how synapse organizing proteins such as leucine rich repeat transmembrane neuronal proteins (LRRTMs) govern brain lamination and plasticity (Obj. 1,) moderate synaptic activity of large networks (Obj. 2), and control synapse numbers via inhibitory factors (Obj. 3). Specific Objective 1: We will investigate the contributions of LRRTM1 and LRRTM2 to regulate lamina-selective synapse development and plasticity. Our preliminary work indicates that LRRTM1 and LRRTM2 are enriched in specific dendritic laminae of the hippocampus, and that deletion of Lrrtm1 in the CA1 impairs plasticity in a layer-specific manner. We will compare the precise contributions of LRRTM1 and LRRTM2 to the development and plasticity of excitatory synapses in the hippocampal CA1 dendritic laminae, in both the developing mouse brain and after acute loss in the adult mouse brain. Specific Objective 2. Excitatory synaptic activity of pyramidal neurons is moderated by feed-forward inhibition by a network of fast-spiking parvalbumin (PV+ve) interneurons. The inhibitory effect of interneurons is dependent on their activation state, which is controlled by excitatory synaptic transmission onto them. We will investigate the mechanisms of excitatory synapse organization on cortical PV+ve interneurons that enables feed-forward inhibition of cortical networks. Specific Objective 3. Recent work in my laboratory indicates that glycophosphatidylinositol anchored glypican4 negatively regulates synapse development by LRRTMs by outcompeting neurexins, the bonafide presynaptic partners of LRRTMs. We found that glypican4 is highly expressed in the axonal mossy fibers from the dentate gyrus that synapse onto thorny excrescences, postsynaptic specializations of CA3. We will assess the potential anti-synaptogenic activities of glypican4 in this circuit using circuit-specific gene modifications, and a range of morphological and functional assays. Significance: My research program will demonstrate how synapses develop and function in specific brain regions, a key step in understanding the molecular mechanisms of the development of precise neural networks in the brain. The transdisciplinary training of HQP in cutting-edge neuroscience techniques will ensure that they are sought after in both industry and academia.