Proper function of the nervous system requires the development and maintenance of appropriate neuronal connectivity and effective communication that is largely mediated by chemical synapses. Deficits in synaptic connectivity, resulting from genetic or epigenetic abnormalities revealed either during development or after acute pharmacological or environmental insult, are likely to contribute significantly to impaired brain function. Regulated exocytosis of classical neurotransmitters, as well as neuropeptides and modulatory neurotrophic factors is proposed to underlie the necessary presynaptic input for effective communication between neurons. The overall goal of the research of this laboratory is to gain a better understanding of the molecular mechanisms which control neuroexocytosis. Moreover, implicit in these studies is the general hypothesis that presynaptic regulation of neurotransmitter release can modulate brain development and function, and consequently that deficiencies in this molecular machinery can play at least a part in the cognitive and behavioral impairments of neuropsychiatric disorders. To address these issues, we have focused on the protein SNAP-25, which we propose plays a regulatory role, as well as its more well-defined part as an integral structural component of the exocytotic protein machinery necessary for vesicle fusion and neurotransmitter release. Our investigations make use of SNAP-25 null and hypomorphic mouse mutants which we have developed in the previous funding of this grant.
In Specific Aim 1 experiments are designed to use Snap25-/- mice to determine the role of neuroexocytosis in axon stabilization and synapse formation.
Specific Aim 2 will use replication defective viral expression systems and Snap25-/- cultured neurons to examine role of sequences that are postranslationally modified and distinguish developmentally regulated SNAP-25 isoforms.
Specific Aim 3 addresses the hypothesis of whether the developmental switch in SNAP-25 isoforms underlines the maturation of synaptic transmission by electrophysiological and neurochemical measurements of SNAP-25b hypomorph mutants. Finally in Specific Aim 4, experiments are designed to examine whether Snap25 heterozygotes that express reduced levels of SNAP-25 are more susceptible to psychotomimetic drugs and thus are a model of genetic vulnerability. If successful this investigation will shed light on the selective roles of SNAP-25 isoforms, the roles they play in the synaptic plasticity required for normal brain function, and how abnormalities in presynaptic mechanisms of neurotransmission may be involved in neuropsychiatric disease.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Asanuma, Chiiko
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of New Mexico
Schools of Medicine
United States
Zip Code
Blakey, Daniel; Wilson, Michael C; Molnár, Zoltán (2012) Termination and initial branch formation of SNAP-25-deficient thalamocortical fibres in heterochronic organotypic co-cultures. Eur J Neurosci 35:1586-94
Scullin, Chessa S; Tafoya, Lawrence C; Wilson, Michael C et al. (2012) Presynaptic residual calcium and synaptic facilitation at hippocampal synapses of mice with altered expression of SNAP-25. Brain Res 1431:1-12
BasuRay, Soumik; Mukherjee, Sanchita; Romero, Elsa et al. (2010) Rab7 mutants associated with Charcot-Marie-Tooth disease exhibit enhanced NGF-stimulated signaling. PLoS One 5:e15351
Scullin, Chessa S; Wilson, Michael C; Partridge, L Donald (2010) Developmental changes in presynaptic Ca(2 +) clearance kinetics and synaptic plasticity in mouse Schaffer collateral terminals. Eur J Neurosci 31:817-26
Corradini, Irene; Verderio, Claudia; Sala, Mariaelvina et al. (2009) SNAP-25 in neuropsychiatric disorders. Ann N Y Acad Sci 1152:93-9
Mazelova, Jana; Ransom, Nancy; Astuto-Gribble, Lisa et al. (2009) Syntaxin 3 and SNAP-25 pairing, regulated by omega-3 docosahexaenoic acid, controls the delivery of rhodopsin for the biogenesis of cilia-derived sensory organelles, the rod outer segments. J Cell Sci 122:2003-13
Tafoya, Lawrence C R; Shuttleworth, C William; Yanagawa, Yuchio et al. (2008) The role of the t-SNARE SNAP-25 in action potential-dependent calcium signaling and expression in GABAergic and glutamatergic neurons. BMC Neurosci 9:105
Bronk, Peter; Deak, Ferenc; Wilson, Michael C et al. (2007) Differential effects of SNAP-25 deletion on Ca2+ -dependent and Ca2+ -independent neurotransmission. J Neurophysiol 98:794-806
Shimada, Masayuki; Yanai, Yoshiari; Okazaki, Tetsuji et al. (2007) Synaptosomal-associated protein 25 gene expression is hormonally regulated during ovulation and is involved in cytokine/chemokine exocytosis from granulosa cells. Mol Endocrinol 21:2487-502
Tafoya, Lawrence C R; Mameli, Manuel; Miyashita, Teiko et al. (2006) Expression and function of SNAP-25 as a universal SNARE component in GABAergic neurons. J Neurosci 26:7826-38

Showing the most recent 10 out of 31 publications