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J. Biol. Chem., Vol. 280, Issue 27, 25769-25779, July 8, 2005

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SNAP-29-mediated Modulation of Synaptic Transmission in Cultured Hippocampal Neurons^*

Ping-Yue Pan¶||, Qian Cai¶||, Lin Lin, Pei-Hua Lu, Shumin Duan**, and Zu-Hang Sheng¶

From the Department of Neurobiology, Shanghai Second Medical University, 280 Chong Qing Nan Road, 200025 Shanghai, China, Institute of Neuroscience and Key Laboratory of Neurobiology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and ^¶Synaptic Function Unit, The Porter Neuroscience Research Center, NINDS, National Institutes of Health, Bethesda, Maryland 20892-3701

Identifying the molecules that regulate both the recycling of synaptic vesicles and the SNARE components required for fusion is critical for elucidating the molecular mechanisms underlying synaptic plasticity. SNAP-29 was initially isolated as a syntaxin-binding and ubiquitously expressed protein. Previous studies have suggested that SNAP-29 inhibits SNARE complex disassembly, thereby reducing synaptic transmission in cultured superior cervical ganglion neurons in an activity-dependent manner. However, the role of SNAP-29 in regulating synaptic vesicle recycling and short-term plasticity in the central nervous system remains unclear. In the present study, we examined the effect of SNAP-29 on synaptic transmission in cultured hippocampal neurons by dual patch clamp whole-cell recording, FM dye imaging, and immunocytochemistry. Our results demonstrated that exogenous expression of SNAP-29 in presynaptic neurons significantly decreased the efficiency of synaptic transmission after repetitive firing within a few minutes under low and moderate frequency stimulations (0.1 and 1 Hz). In contrast, SNAP-29 did not affect the density of synapses and basal synaptic transmission. Whereas neurotransmitter release was unaffected during intensive stimulation, recovery after synaptic depression was impaired by SNAP-29. Furthermore, knockdown of SNAP-29 expression in neurons by small interfering RNA increased the efficiency of synaptic transmission during repetitive firing. These findings suggest that SNAP-29 acts as a negative modulator for neurotransmitter release, probably by slowing recycling of the SNARE-based fusion machinery and synaptic vesicle turnover.

Received for publication, March 2, 2005 , and in revised form, May 6, 2005.

^* This work was supported in part by the intramural research program of NINDS National Institutes of Health (Z.-H. S.) and Major State Basic Research Program of China Grant G200077800 and National Natural Science Foundation of China Grant 30321002 (to S. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| Graduate students of the National Institutes of Health-Shanghai Second Medical University Joint Ph.D. Program in Neuroscience partially supported by Chinese National Outstanding Young Scientists Foundation Grant 39928001 and Shanghai Science Technology Development Foundation Grant 01JC14023 and 03ZR14040 (to L. L.).

^** To whom correspondence may be addressed. E-mail: shumin{at}ion.ac.cn. To whom correspondence may be addressed: Synaptic Function Unit, The Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 35 Convent Dr., Rm. 3B203, Bethesda, MD 20892-3701. Tel.: 301-435-4596; Fax: 301-480-5763; E-mail: shengz{at}ninds.nih.gov.

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