Excitation-transcription coupling via calcium/calmodulindependent protein kinase/ERK1/2 signaling mediates the coordinate induction of VGLUT2 and Narp triggered by a prolonged increase in glutamatergic synaptic activity

Abstract

Homeostatic scaling of glutamatergic and GABAergic transmission is triggered by prolonged alterationsin synaptic neuronal activity. We have previously described a presynaptic mechanism for synaptic homeostasis and plasticity that involves scaling the level of vesicular glutamate (VGLUT1) and γ-aminobutyric acid (GABA) (VGAT) transporterbiosynthesis. Thesemoleculardeterminantsofvesiclefilling and quantal size are regulated by neuronal activity in an opposite mannerandbi-directionally.Here, wereportthatastrikinginduction of VGLUT2 mRNA and synaptic protein is triggered by a prolonged increase in glutamatergic synaptic activity in mature neocortical neuronal networks in vitro together with two determinants of inhibitory synaptic strength, the neuronal activity-regulated pentraxin (Narp), andglutamatedecarboxylase(GAD65).Activity-dependentinduction of VGLUT2 and Narp exhibits a similar intermediate-early gene responsethatisblockedbyactinomycinDandtetrodotoxin,byinhibitors of ionotropic glutamate receptors and L-type voltage-gated calcium channels, and is dependent on downstream signaling via calmodulin, calcium/calmodulin- dependentproteinkinase(CaMK)and extracellular signal-regulated kinase 1/2 (ERK1/2). The co-induction of VGLUT2 and Narp triggered by prolonged γ-aminobutyric acid type A receptor blockade is independent of brain-derived nerve growth factor and TrkB receptor signaling. VGLUT2 protein induction occurs on a subset of cortically derived synaptic vesicles in excitatory synapses on somata and dendritic processes of multipolar GABAergic interneurons,recognized sites for the clustering of α-amino-3-hydroxy-5- methyl-4-isoxazolepropionate glutamate receptors byNarp.We propose that VGLUT2 and Narpinduction by excitation transcription coupling leads to increased glutamatergic transmission at synapses on GABAergic inhibitory feedback neurons as part of a coordinated program of Ca2+-signal transcription involved in mechanisms of homeostatic plasticity after prolonged hyperactivity. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.