Gabapentin Receptor Alpha2delta-1 is a Neuronal Thrombospondin Receptor Responsible for Excitatory CNS Synaptogenesis

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2009 Oct 13

PMID 19818485

Citations 494

Authors

Cagla Eroglu

Nicola J Allen

Michael W Susman

Nancy A ORourke

Chan Young Park

Engin Ozkan

Chandrani Chakraborty

Sara B Mulinyawe

Douglas S Annis

Andrew D Huberman

Eric M Green

Jack Lawler

Ricardo Dolmetsch

K Christopher Garcia

Stephen J Smith

Z David Luo

Arnon Rosenthal

Deane F Mosher

Ben A Barres

Affiliations

Soon will be listed here.

Abstract

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 alpha2delta-1, the receptor for the anti-epileptic and analgesic drug gabapentin. We show that the VWF-A domain of alpha2delta-1 interacts with the epidermal growth factor-like repeats common to all thrombospondins. alpha2delta-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 alpha2delta-1 and powerfully inhibits excitatory synapse formation in vitro and in vivo. These findings identify alpha2delta-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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