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The Journal of Neuroscience, December 27, 2006, 26(52):13493-13504; doi:10.1523/JNEUROSCI.3519-06.2006

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Cellular/Molecular
Synaptotagmin-2 Is Essential for Survival and Contributes to Ca²⁺ Triggering of Neurotransmitter Release in Central and Neuromuscular Synapses

Zhiping P. Pang,¹ Ernestina Melicoff,⁵ Daniel Padgett,¹ Yun Liu,¹ Andrew F. Teich,⁵ Burton F. Dickey,⁵ Weichun Lin,^1,3 Roberto Adachi,⁵ and Thomas C. Südhof^1,2,4

¹Center for Basic Neuroscience, ²Departments of Molecular Genetics and ³Cell Biology, and ⁴Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, and ⁵Department of Pulmonary Medicine, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Correspondence should be addressed to either of the following: Roberto Adachi at the above address, Email: radachi{at}mdanderson.org; or Thomas C. Südhof at the above address, Email: thomas.sudhof{at}utsouthwestern.edu

Biochemical and genetic data suggest that synaptotagmin-2 functions as a Ca²⁺ sensor for fast neurotransmitter release in caudal brain regions, but animals and/or synapses lacking synaptotagmin-2 have not been examined. We have now generated mice in which the 5' end of the synaptotagmin-2 gene was replaced by lacZ. Using ß-galactosidase as a marker, we show that, consistent with previous studies, synaptotagmin-2 is widely expressed in spinal cord, brainstem, and cerebellum, but is additionally present in selected forebrain neurons, including most striatal neurons and some hypothalamic, cortical, and hippocampal neurons. Synaptotagmin-2-deficient mice were indistinguishable from wild-type littermates at birth, but subsequently developed severe motor dysfunction, and perished at 3 weeks of age. Electrophysiological studies in cultured striatal neurons revealed that the synaptotagmin-2 deletion slowed the kinetics of evoked neurotransmitter release without altering the total amount of release. In contrast, synaptotagmin-2-deficient neuromuscular junctions (NMJs) suffered from a large reduction in evoked release and changes in short-term synaptic plasticity. Furthermore, in mutant NMJs, the frequency of spontaneous miniature release events was increased both at rest and during stimulus trains. Viewed together, our results demonstrate that the synaptotagmin-2 deficiency causes a lethal impairment in synaptic transmission in selected synapses. This impairment, however, is less severe than that produced in forebrain neurons by deletion of synaptotagmin-1, presumably because at least in NMJs, synaptotagmin-1 is coexpressed with synaptotagmin-2, and both together mediate fast Ca²⁺-triggered release. Thus, synaptotagmin-2 is an essential synaptotagmin isoform that functions in concert with other synaptotagmins in the Ca²⁺ triggering of neurotransmitter release.

Key words: asynchronous release; endplate; neuromuscular junction; striatum; synapse; synaptotagmin

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Received Aug. 14, 2006; revised Oct. 10, 2006; accepted Nov. 21, 2006.

Correspondence should be addressed to either of the following: Roberto Adachi at the above address, Email: radachi{at}mdanderson.org; or Thomas C. Südhof at the above address, Email: thomas.sudhof{at}utsouthwestern.edu

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