title: 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 gamma-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), and glutamate decarboxylase (GAD65). Activity-dependent induction 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 gamma-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 alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate glutamate receptors by Narp. We propose that VGLUT2 and Narp induction by excitation-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.
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
authors.forename: Sukhjeevan
authors.initials: S
authors.lastname: Doyle
authors.forename: Slovénie
authors.initials: S
authors.lastname: Pyndiah
authors.forename: Stéphanie
authors.initials: S
authors.lastname: De Gois
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Erickson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D002478:Cells, Cultured; D018756:GABA Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D018507:Gene Expression Regulation, Developmental; D005968:Glutamate Decarboxylase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009473:Neuronal Plasticity; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011724:Pyridazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013572:Synaptic Vesicles / Q000378:metabolism; D014158:Transcription, Genetic; D050598:Vesicular Glutamate Transport Protein 1 / Q000235:genetics / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics* / Q000378:metabolism; D000099153:Pentraxins
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002097:C-Reactive Protein; D002118:Calcium; D020746:Calcium Channels, L-Type; D002147:Calmodulin; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D005968:Glutamate Decarboxylase; D018698:Glutamic Acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009419:Nerve Tissue Proteins; D011724:Pyridazines; D012333:RNA, Messenger; D020917:Receptor, trkA; D011963:Receptors, GABA-A; D050598:Vesicular Glutamate Transport Protein 1; D050599:Vesicular Glutamate Transport Protein 2; D000099153:Pentraxins; C493475:Slc17a6 protein, rat; C493466:Slc17a7 protein, rat; C049853:gabazine; C401141:glutamate decarboxylase 2