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The Journal of Neuroscience, September 1, 2001, 21(17):6588-6596

Chronic Blockade of Glutamate Receptors Enhances Presynaptic Release and Downregulates the Interaction between Synaptophysin-Synaptobrevin-Vesicle-Associated Membrane Protein 2

Alberto Bacci¹, Silvia Coco¹, Elena Pravettoni¹, Ursula Schenk¹, Simona Armano¹, Carolina Frassoni², Claudia Verderio¹, Pietro De Camilli³, and Michela Matteoli¹

¹ Consiglio Nazionale delle Ricerche, Cellular and Molecular Pharmacology and "B. Ceccarelli" Centers, Department of Medical Pharmacology, University of Milan, 20129 Milan, Italy, ² Neurological Institute "C. Besta", 20133 Milan, Italy and ³ Howard Hughes Medical Institute and Department of Cell Biology, Yale School of Medicine, New Haven, Connecticut 06510

During development of neuronal circuits, presynaptic and postsynaptic functions are adjusted in concert, to optimize interneuronal signaling. We have investigated whether activation of glutamate receptors affects presynaptic function during synapse formation, when constitutive synaptic vesicle recycling is downregulated. Using primary cultures of hippocampal neurons as a model system, we have found that chronic exposure to both NMDA and non-NMDA glutamate receptor blockers during synaptogenesis produces an increase in miniature EPSC (mEPSC) frequency, with no significant changes in mEPSC amplitude or in the number of synapses. Enhanced synaptic vesicle recycling, selectively in glutamatergic nerve terminals, was confirmed by the increased uptake of antibodies directed against the lumenal domain of synaptotagmin. No increased uptake was detected in neuronal cultures grown in the chronic presence of TTX, speaking against an indirect effect caused by decreased electrical activity. Enhanced mEPSC frequency correlated with a reduction of synaptophysin-synaptobrevin-vesicle-associated membrane protein 2 (VAMP2) complexes detectable by immunoprecipitation. Intracellular perfusion with a peptide that inhibits the binding of synaptophysin to synaptobrevin-VAMP2 induced a remarkable increase of mEPSC frequency in control but not in glutamate receptor blocker-treated neurons. These findings suggest that activation of glutamate receptors plays a role in the downregulation of the basal rate of synaptic vesicle recycling that accompanies synapse formation. They also suggest that one of the mechanisms through which this downregulation is achieved is an increased interaction of synaptophysin with synaptobrevin-VAMP2.

Key words: hippocampal neurons; glutamate receptors; synaptic vesicle recycling; presynaptic release; synaptobrevin-VAMP2; synaptophysin

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21176588-09$05.00/0

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