期刊
CELL
卷 139, 期 2, 页码 380-392出版社
CELL PRESS
DOI: 10.1016/j.cell.2009.09.025
关键词
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资金
- National Institute of Drug Addiction [DA15043]
- National Heart, Lung and Blood Institute [HL49081]
- National Institute of Neurological Disorders and Stroke
- National Institute of Dental and Craniofacial Research [NS40135, DE14545]
- Human Frontiers Scientific Program long-term fellowships
- Helen Hay Whitney postdoctoral fellowship
Synapses are asymmetric cellular adhesions that are critical for nervous system development and function, but the mechanisms that induce their formation are not well understood. We have previously identified thrombospondin as an astrocyte-secreted protein that promotes central nervous system (CNS) synaptogenesis. Here, we identify the neuronal thrombospondin receptor involved in CNS synapse formation as alpha 2 delta-1, the receptor for the anti-epileptic and analgesic drug gabapentin. We show that the VWF-A domain of alpha 2 delta-1 interacts with the epidermal growth factor-like repeats common to all thrombospondins. alpha 2 delta-1 overexpression increases synaptogenesis in vitro and in vivo and is required postsynaptically for thrombospondin-and astrocyte-induced synapse formation in vitro. Gabapentin antagonizes thrombospondin binding to alpha 2 delta-1 and powerfully inhibits excitatory synapse formation in vitro and in vivo. These findings identify alpha 2 delta-1 as a receptor involved in excitatory synapse formation and suggest that gabapentin may function therapeutically by blocking new synapse formation.
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