Determining the molecular events that produce and regulate the release of neurotransmitters is one of the central goals of molecular neurobiology. Defining these events, and how they are altered with experience and in disease, will provide an understanding of normal processes such as learning and serve as the biological basis for developing new therapies for mental illness, neurological disorders and addiction. The work proposed here addresses the function of Synaptic Vesicle Protein 2 (SV2), a glycoprotein constituent of all neurotransmitter-containing (synaptic) vesicles. In the last funding period we demonstrated that Synaptic Vesicle Protein 2 (SV2) is an essential modulator of neurotransmission. Loss of SV2A reduces neurotransmission in hippocampal and cortical neurons, and reduces the size of the readily releasable pool of vesicles in chromaffin cells. Reduced neurotransmission is not due to morphological changes or to a decrease in morphologically """"""""docked"""""""" synaptic vesicles. Together these results suggest that SV2 is a positive modulator of vesicle priming that acts after vesicle attachment at the plasma membrane. We propose to use SV2 knockout mice to determine SV2's molecular function in fast neurotransmission and to resolve differences in isoform functioning.
Our specific aims are: ? 1. To determine how neurotransmission is altered in cultured hippocampal neurons from SV2 KOs. ? 2. To use exogeneous protein expression in hippocampal neurons to test hypotheses of SV2 function. ? 3. To test the hypothesis that SV2B plays a crucial role in ribbon synapse maintenance and/or functioning. ? ?
| Nowack, Amy; Malarkey, Erik B; Yao, Jia et al. (2011) Levetiracetam reverses synaptic deficits produced by overexpression of SV2A. PLoS One 6:e29560 |
| Sgro, Allyson E; Nowak, Amy L; Austin, Naola S et al. (2011) A high-throughput method for generating uniform microislands for autaptic neuronal cultures. J Neurosci Methods 198:230-5 |
| Nowack, Amy; Yao, Jia; Custer, Kenneth L et al. (2010) SV2 regulates neurotransmitter release via multiple mechanisms. Am J Physiol Cell Physiol 299:C960-7 |
| Yao, Jia; Nowack, Amy; Kensel-Hammes, Patricia et al. (2010) Cotrafficking of SV2 and synaptotagmin at the synapse. J Neurosci 30:5569-78 |
| Morgans, Catherine W; Kensel-Hammes, Patricia; Hurley, James B et al. (2009) Loss of the Synaptic Vesicle Protein SV2B results in reduced neurotransmission and altered synaptic vesicle protein expression in the retina. PLoS One 4:e5230 |
| Yao, Jia; Bajjalieh, Sandra M (2009) SVOP is a nucleotide binding protein. PLoS One 4:e5315 |
| Yao, Jia; Bajjalieh, Sandra M (2008) Synaptic vesicle protein 2 binds adenine nucleotides. J Biol Chem 283:20628-34 |
| Custer, Kenneth L; Austin, Naola S; Sullivan, Jane M et al. (2006) Synaptic vesicle protein 2 enhances release probability at quiescent synapses. J Neurosci 26:1303-13 |
| Schivell, Amanda E; Mochida, Sumiko; Kensel-Hammes, Patricia et al. (2005) SV2A and SV2C contain a unique synaptotagmin-binding site. Mol Cell Neurosci 29:56-64 |
| Lynch, Berkley A; Lambeng, Nathalie; Nocka, Karl et al. (2004) The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A 101:9861-6 |
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