Our long-term goal is to gain a molecular understanding of the mechanisms that regulate the development and function of glutamatergic synapses in the mammalian brain. Most glutamatergic synapses share certain features, such as the presence of postsynaptic AMPA and NMDA receptors. At the same time, there is great diversity in the structure and function of glutamatergic synapses depending on the identity of the pre- and postsynaptic neuron. For example, CA3 neurons in the hippocampus receive highly facilitating mossy fiber synapses from Dentate Gyrus (DG) axons on specialized spines, called thorny excrescences. The same neurons receive association/commissural (A/C) neuron synapses on classical spines that are not highly facilitating. The CA3 A/C synapses share many structural features and functional properties with CA3-CA1 Schaffer collateral synapses, suggesting that they may be specified by common molecular mechanisms. Our preliminary studies suggest that the leucine rich repeat containing transmembrane protein LRRTM2 plays a critical role in regulating glutamatergic synapses in the hippocampus. In this proposal we wish to determine if LRRTM2 regulates specific classes of glutamatergic synapses in the hippocampus, and whether it regulates synapse structure and function in vivo.

Public Health Relevance

The goal of this project is to understand the role of a class of cell surface proteins in the establishment and function of excitatory synaptic connections. Several childhood neurological disorders, such as Autism, Rett Syndrome, and X-linked mental retardation are characterized by defects in synaptic connectivity and function. The findings of this project should guide efforts to better understand and develop therapeutic strategies for these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS067216-03
Application #
8206744
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Talley, Edmund M
Project Start
2010-01-15
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$318,010
Indirect Cost
$103,635
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
de Wit, Joris; Ghosh, Anirvan (2016) Specification of synaptic connectivity by cell surface interactions. Nat Rev Neurosci 17:22-35
Bourane, Steeve; Duan, Bo; Koch, Stephanie C et al. (2015) Gate control of mechanical itch by a subpopulation of spinal cord interneurons. Science 350:550-4
Savas, Jeffrey N; Ribeiro, Luís F; Wierda, Keimpe D et al. (2015) The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors. Neuron 87:764-80
de Wit, Joris; Ghosh, Anirvan (2014) Control of neural circuit formation by leucine-rich repeat proteins. Trends Neurosci 37:539-50
Savas, Jeffrey N; De Wit, Joris; Comoletti, Davide et al. (2014) Ecto-Fc MS identifies ligand-receptor interactions through extracellular domain Fc fusion protein baits and shotgun proteomic analysis. Nat Protoc 9:2061-74
O'Sullivan, Matthew L; Martini, Francesca; von Daake, Sventja et al. (2014) LPHN3, a presynaptic adhesion-GPCR implicated in ADHD, regulates the strength of neocortical layer 2/3 synaptic input to layer 5. Neural Dev 9:7
de Wit, Joris; O'Sullivan, Matthew L; Savas, Jeffrey N et al. (2013) Unbiased discovery of glypican as a receptor for LRRTM4 in regulating excitatory synapse development. Neuron 79:696-711
DeNardo, Laura A; de Wit, Joris; Otto-Hitt, Stefanie et al. (2012) NGL-2 regulates input-specific synapse development in CA1 pyramidal neurons. Neuron 76:762-75
Sylwestrak, Emily L; Ghosh, Anirvan (2012) Elfn1 regulates target-specific release probability at CA1-interneuron synapses. Science 338:536-40
O'Sullivan, Matthew L; de Wit, Joris; Savas, Jeffrey N et al. (2012) FLRT proteins are endogenous latrophilin ligands and regulate excitatory synapse development. Neuron 73:903-10

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