The long-term goal of this research program is to elucidate the cellular and molecular mechanisms that participate in the formation and function of a synaptic contact. The present proposal focuses on the role of cell adhesion in the formation of three major synaptic specializations: presynaptic terminals, active zones, and somatic spines. The primary hypothesis is that the development of adhesive linkages mediated by cell-cell and cell-matrix interactions are required for the structural organization and function of the synapse. In addition, a precise control of surface adhesion is needed for the structural modification of the synaptic junction in response to physiological stimuli. Utilizing the calyx-type synapse of the chick ciliary ganglion as an experimental model system and a retroviral system to induce molecular perturbations during development, this study will focus on the role of two families of adhesion molecules, namely the cadherins and the integrins. These molecules have been selected because of their prominent adhesive activity and expression pattern in the ciliary ganglion. The role of N-cadherin and integrins (beta1 and beta4) in the structural organization of the synapse will be investigated by perturbing their adhesive properties with wild type and mutated molecules that exert dominant negative effects. The consequences of interfering with cell adhesion will be evaluated morphologically, by analyzing the structure of the synapse at the light confocal and electron microscopic level, and functionally by assessing electrophysiologically the efficacy of synaptic transmission and the properties of the electrical currents of the ciliary neurons. The information gained from this study will lead to a better understanding of synaptogenesis and the structural requirements for synaptic function. As a variety of psychiatric and neurological disorders are believed to arise from synaptic malfunction, these studies will contribute basic knowledge toward elucidation of cellular and molecular mechanisms underlying neuropathological conditions.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-7 (01))
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Talley, Edmund M
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Sloan-Kettering Institute for Cancer Research
New York
United States
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Bruses, Juan L (2011) N-cadherin regulates primary motor axon growth and branching during zebrafish embryonic development. J Comp Neurol 519:1797-815
Brusés, Juan L (2010) Identification of gene transcripts expressed by postsynaptic neurons during synapse formation encoding cell surface proteins with presumptive synaptogenic activity. Synapse 64:47-60
Marrs, Glen S; Theisen, Christopher S; Brusés, Juan L (2009) N-cadherin modulates voltage activated calcium influx via RhoA, p120-catenin, and myosin-actin interaction. Mol Cell Neurosci 40:390-400
Bruses, Juan L (2006) N-cadherin signaling in synapse formation and neuronal physiology. Mol Neurobiol 33:237-52
Rubio, Maria E; Curcio, Christine; Chauvet, Norbert et al. (2005) Assembly of the N-cadherin complex during synapse formation involves uncoupling of p120-catenin and association with presenilin 1. Mol Cell Neurosci 30:118-30
Tricaud, Nicolas; Perrin-Tricaud, Claire; Bruses, Juan L et al. (2005) Adherens junctions in myelinating Schwann cells stabilize Schmidt-Lanterman incisures via recruitment of p120 catenin to E-cadherin. J Neurosci 25:3259-69
Rubio, Maria E; Curcio, Christine; Chauvet, Norbert et al. (2005) Assembly of the N-cadherin complex during synapse formation involves uncoupling of p120-catenin and association with presenilin 1. Mol Cell Neurosci 30:611-23
Perrier, Anselme L; Tabar, Viviane; Barberi, Tiziano et al. (2004) Derivation of midbrain dopamine neurons from human embryonic stem cells. Proc Natl Acad Sci U S A 101:12543-8
Piccoli, Giuseppe; Rutishauser, Urs; Bruses, Juan L (2004) N-cadherin juxtamembrane domain modulates voltage-gated Ca2+ current via RhoA GTPase and Rho-associated kinase. J Neurosci 24:10918-23
Bruses, Juan L; Chauvet, Norbert; Rubio, Maria E et al. (2002) Polysialic acid and the formation of oculomotor synapses on chick ciliary neurons. J Comp Neurol 446:244-56