Brain development requires orchestrated formation of connections between nerve cells. These synaptic connections are the main units of communication in the brain, where chemical neurotransmitter signaling occurs. This proposal is on synaptic organizing proteins, genes that function as master regulators of synaptic development. Such proteins alone can trigger formation of nerve cell connections. In preliminary studies, from an unbiased screen we identified a new protein that triggers development of presynaptic connections in contacting nerve cell processes. It is one of a family of 3 highly related proteins. The proposed experiments will assess the ability of these 3 synaptic organizing proteins to drive formation of nerve cell connections of different neurotransmitter types, and will identify protein domains responsible. These novel synaptic organizing proteins can be cleared by extracellular proteolysis. Preliminary data suggests that cleavage abolishes synaptic organizing activity;thus we will study how cleavage is regulated. Finally, a major aim is to use a combination of mouse molecular genetics, fluorescence imaging, biochemistry, electrophysiology, and behavioral assays to determine the importance of these genes in brain development and synaptic function. This combined in vivo approach will allow an understanding of how these genes contribute to brain wiring, synaptic composition, structure, and function, and how changes in specific synapses result in behavioral changes. Such approaches often result in useful models for psychiatric disorders. The central hypothesis is that these genes are crucial for organizing synaptic development, for recruiting molecular components essential for proper synaptic structure and function in brain circuits important for cognition. Variation in one of these genes is linked to word recall ability, and lower organisms lacking the single homologous gene are deficient in learning. Furthermore, variants in the major synaptic organizing gene families studied to date, neuroligins and neurexins, predispose to autism spectrum disorders, schizophrenia, and mental retardation. Thus, in studying these synaptic organizing genes, we hope to increase our understanding of the molecular basis for cognitive disorders and to help design rational drug treatments. As triggers for building synaptic connections, these genes may also have implications for a number of neurological disorders from epilepsy and stroke to Alzheimer's and Parkinson's diseases. It may be possible to harness the ability of these genes to trigger formation of nerve cell connections to repair and regenerate the lost and injured connections in these debilitating disorders.

Public Health Relevance

The goal is to understand how specific genes control the wiring and function of brain cells in health and disease. Variations in the gene under study influence word recall ability, and lower organisms lacking this gene are deficient in learning. The proposed research will reveal how this gene organizes connections between brain cells, controlling their partner choice, structure, biochemical composition and function to regulate behavior, and how alterations is such genes predispose to psychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH070860-07
Application #
8199052
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Asanuma, Chiiko
Project Start
2004-04-01
Project End
2012-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
7
Fiscal Year
2012
Total Cost
$252,317
Indirect Cost
$17,313
Name
University of British Columbia
Department
Type
DUNS #
251949962
City
Vancouver
State
BC
Country
Canada
Zip Code
V6 1-Z3
Coles, Charlotte H; Mitakidis, Nikolaos; Zhang, Peng et al. (2014) Structural basis for extracellular cis and trans RPTP? signal competition in synaptogenesis. Nat Commun 5:5209
Pettem, Katherine L; Yokomaku, Daisaku; Takahashi, Hideto et al. (2013) Interaction between autism-linked MDGAs and neuroligins suppresses inhibitory synapse development. J Cell Biol 200:321-36
Takahashi, Hideto; Craig, Ann Marie (2013) Protein tyrosine phosphatases PTPýý, PTPýý, and LAR: presynaptic hubs for synapse organization. Trends Neurosci 36:522-34
Pettem, Katherine L; Yokomaku, Daisaku; Luo, Lin et al. (2013) The specific *-neurexin interactor calsyntenin-3 promotes excitatory and inhibitory synapse development. Neuron 80:113-28
Woo, Jooyeon; Kwon, Seok-Kyu; Nam, Jungyong et al. (2013) The adhesion protein IgSF9b is coupled to neuroligin 2 via S-SCAM to promote inhibitory synapse development. J Cell Biol 201:929-44
Takahashi, Hideto; Katayama, Kei-Ichi; Sohya, Kazuhiro et al. (2012) Selective control of inhibitory synapse development by Slitrk3-PTPýý trans-synaptic interaction. Nat Neurosci 15:389-98, S1-2
Gauthier, Julie; Siddiqui, Tabrez J; Huashan, Peng et al. (2011) Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. Hum Genet 130:563-73
Takahashi, Hideto; Arstikaitis, Pamela; Prasad, Tuhina et al. (2011) Postsynaptic TrkC and presynaptic PTP? function as a bidirectional excitatory synaptic organizing complex. Neuron 69:287-303
Siddiqui, Tabrez J; Craig, Ann Marie (2011) Synaptic organizing complexes. Curr Opin Neurobiol 21:132-43
Siddiqui, Tabrez J; Pancaroglu, Raika; Kang, Yunhee et al. (2010) LRRTMs and neuroligins bind neurexins with a differential code to cooperate in glutamate synapse development. J Neurosci 30:7495-506

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