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VEGF modulates NMDA receptors activity in cerebellar granule cells through Src-family kinases before synapse formation.

ABSTRACT: NMDA type glutamate receptors (NMDARs) are best known for their role in synaptogenesis and synaptic plasticity. Much less is known about their developmental role before neurons form synapses. We report here that VEGF, which promotes migration of granule cells (GCs) during postnatal cerebellar development, enhances NMDAR-mediated currents and Ca(2+) influx in immature GCs before synapse formation. The VEGF receptor Flk1 forms a complex with the NMDAR subunits NR1 and NR2B. In response to VEGF, the number of Flk1/NR2B coclusters on the cell surface increases. Stimulation of Flk1 by VEGF activates Src-family kinases, which increases tyrosine phosphorylation of NR2B. Inhibition of Src-family kinases abolishes the VEGF-dependent NR2B phosphorylation and amplification of NMDAR-mediated currents and Ca(2+) influx in GCs. These findings identify VEGF as a modulator of NMDARs before synapse formation and highlight a link between an activity-independent neurovascular guidance cue (VEGF) and an activity-regulated neurotransmitter receptor (NMDAR).

SUBMITTER: Meissirel C

PROVIDER: S-EPMC3158143 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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VEGF modulates NMDA receptors activity in cerebellar granule cells through Src-family kinases before synapse formation.

Meissirel Claire C Ruiz de Almodovar Carmen C Knevels Ellen E Coulon Cathy C Chounlamountri Naura N Segura Inmaculada I de Rossi Pierre P Vinckier Stefan S Anthonis Kristof K Deléglise Bérangère B de Mol Maria M Ali Carine C Dassonville Karel K Loyens Ellen E Honnorat Jérôme J Michotte Yvette Y Rogemond Véronique V Smolders Ilse I Voets Thomas T Vivien Denis D Vanden Berghe Pieter P Van den Bosch Ludo L Robberecht Wim W Chédotal Alain A Oliviero Salvatore S Dewerchin Mieke M Schmucker Dietmar D Thomasset Nicole N Salin Paul P Carmeliet Peter P

Proceedings of the National Academy of Sciences of the United States of America 20110729 33

NMDA type glutamate receptors (NMDARs) are best known for their role in synaptogenesis and synaptic plasticity. Much less is known about their developmental role before neurons form synapses. We report here that VEGF, which promotes migration of granule cells (GCs) during postnatal cerebellar development, enhances NMDAR-mediated currents and Ca(2+) influx in immature GCs before synapse formation. The VEGF receptor Flk1 forms a complex with the NMDAR subunits NR1 and NR2B. In response to VEGF, th ...[more]

PMID: 21804034

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Project description:UnlabelledAt birth, each mammalian skeletal muscle fiber is innervated by multiple motor neurons, but in a few weeks, all but one of those axons retracts (Redfern, 1970) and differential activity between inputs controls this phenomenon (Personius and Balice-Gordon, 2001; Sanes and Lichtman, 2001; Personius et al., 2007; Favero et al., 2012). Acetylcholine, the primary neuromuscular transmitter, has long been presumed to mediate this activity-dependent process (O'Brien et al., 1978), but glutamatergic transmission also occurs at the neuromuscular junction (Berger et al., 1995; Grozdanovic and Gossrau, 1998; Mays et al., 2009). To test the role of neuromuscular NMDA receptors, we assessed their contribution to muscle calcium fluxes in mice and tested whether they influence removal of excess innervation at the end plate. Developmental synapse pruning was slowed by reduction of NMDA receptor activation or expression and by reduction of glutamate production. Conversely, pruning is accelerated by application of exogenous NMDA. We also found that NMDA induced increased muscle calcium only during the first 2 postnatal weeks. Therefore, neuromuscular NMDA receptors play previously unsuspected roles in neuromuscular activity and synaptic pruning during development.Significance statementIn normal adult muscle, each muscle fiber is innervated by a single axon, but at birth, fibers are multiply innervated. Elimination of excess connections requires neural activity; because the neuromuscular junction (NMJ) is a cholinergic synapse, acetylcholine has been assumed to be the critical mediator of activity. However, glutamate receptors are also expressed at the NMJ. We found that axon removal in mice is slowed by pharmacological and molecular manipulations that decrease signaling through neuromuscular NMDA receptors, whereas application of exogenous NMDA at the NMJ accelerates synapse elimination and increases muscle calcium levels during the first 2 postnatal weeks. Therefore, neuromuscular NMDA receptors play previously unsuspected roles in neuromuscular activity and elimination of excess synaptic input during development.

Dataset Information

VEGF modulates NMDA receptors activity in cerebellar granule cells through Src-family kinases before synapse formation.

Publications

VEGF modulates NMDA receptors activity in cerebellar granule cells through Src-family kinases before synapse formation.

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