Trans-synaptic interaction of GluRdelta2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum.
Elucidation of molecular mechanisms that regulate synapse formation is required for the understanding of neural wiring, higher brain functions, and mental disorders. Despite the wealth of in vitro information, fundamental questions about how glutamatergic synapses are formed in the mammalian brain remain unanswered. Glutamate receptor (GluR) delta2 is essential for cerebellar synapse formation in vivo. Here, we show that the N-terminal domain (NTD) of GluRdelta2 interacts with presynaptic neurexins (NRXNs) through cerebellin 1 precursor protein (Cbln1). The synaptogenic activity of GluRdelta2 is abolished in cerebellar primary cultures from Cbln1 knockout mice and is restored by recombinant Cbln1. Knockdown of NRXNs in cerebellar granule cells also hinders the synaptogenic activity of GluRdelta2. Both the NTD of GluRdelta2 and the extracellular domain of NRXN1beta suppressed the synaptogenic activity of Cbln1 in cerebellar primary cultures and in vivo. These results suggest that GluRdelta2 mediates cerebellar synapse formation by interacting with presynaptic NRXNs through Cbln1.
Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
Takeshi
T
Uemura
Sung-Jin
SJ
Lee
Misato
M
Yasumura
Tomonori
T
Takeuchi
Tomoyuki
T
Yoshida
Moonjin
M
Ra
Ryo
R
Taguchi
Kenji
K
Sakimura
Masayoshi
M
Mishina
D000818:Animals; D002135:Calcium-Binding Proteins; D002460:Cell Line; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000378:metabolism*; D013569:Synapses
D002135:Calcium-Binding Proteins; C092370:Cbln1 protein, mouse; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; C527193:Nrxn1 protein, mouse; D011498:Protein Precursors; D017470:Receptors, Glutamate; C107913:glutamate receptor delta 2