Excitation-Transcription Coupling via Calcium/Calmodulin-dependent 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 alterations in 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 ␥-aminobutyric acid (GABA) (VGAT) transporter biosynthesis. These molecular determinants of vesicle filling and quantal size are regulated by neuronal activity in an opposite manner and bi-directionally. Here, we report that a striking induction 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 response that is blocked by actinomycin D and tetrodotoxin, by inhibitors of ionotropic glutamate receptors and L-type voltage-gated calcium channels, and is dependent on downstream signaling via calmodulin, calcium/calmodulin-dependent protein kinase (CaMK) and extracellular signal-regulated kinase 1/2 (ERK1/2). The co-induction of VGLUT2 and Narp triggered by prolonged ␥-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 ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionate glutamate receptors byNarp.WeproposethatVGLUT2andNarpinductionbyexcitation-transcription coupling leads to increased glutamatergic transmission at synapses on GABAergic inhibitory feedback neurons as part of a coordinated program of Ca 2؉ -signal transcription involved in mechanisms of homeostatic plasticity after prolonged hyperactivity.Homeostatic plasticity is an adaptive response of neocortical and hippocampal neuronal networks after prolonged changes in synaptic activity that scales the strength of excitatory and inhibitory synapses to stabilize the firing rate of pyramidal neurons (1-3). Post-synaptic alterations in AMPA 2 glutamate and GABA A receptor density is thought to account for homeostatic scaling of miniature excitatory and inhibitory postsynaptic current amplitude (4 -10). However, recent evidence has established that in mature neurons, homeostatic plasticity also includes the presynaptic scaling of quantal size; i.e. the amount of glutamate and GABA released from individual synaptic vesicles (11-15). Variations in the quantal size of glutamate released at mammalian excitatory synapses in vivo is due to differences in the concentration of glutamate within vesicles (Ref. 16, but see Ref. 17). Indeed, activity-dependent scaling the level of gene transcription for the vesicular glutamate and GABA transporters (VGLUT1 and VGAT) is a...

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