title: Activity-Dependent Bidirectional Regulation of GAD Expression in a Homeostatic Fashion Is Mediated by BDNF-Dependent and Independent Pathways.
abstract: Homeostatic synaptic plasticity, or synaptic scaling, is a mechanism that tunes neuronal transmission to compensate for prolonged, excessive changes in neuronal activity. Both excitatory and inhibitory neurons undergo homeostatic changes based on synaptic transmission strength, which could effectively contribute to a fine-tuning of circuit activity. However, gene regulation that underlies homeostatic synaptic plasticity in GABAergic (GABA, gamma aminobutyric) neurons is still poorly understood. The present study demonstrated activity-dependent dynamic scaling in which NMDA-R (N-methyl-D-aspartic acid receptor) activity regulated the expression of GABA synthetic enzymes: glutamic acid decarboxylase 65 and 67 (GAD65 and GAD67). Results revealed that activity-regulated BDNF (brain-derived neurotrophic factor) release is necessary, but not sufficient, for activity-dependent up-scaling of these GAD isoforms. Bidirectional forms of activity-dependent GAD expression require both BDNF-dependent and BDNF-independent pathways, both triggered by NMDA-R activity. Additional results indicated that these two GAD genes differ in their responsiveness to chronic changes in neuronal activity, which could be partially caused by differential dependence on BDNF. In parallel to activity-dependent bidirectional scaling in GAD expression, the present study further observed that a chronic change in neuronal activity leads to an alteration in neurotransmitter release from GABAergic neurons in a homeostatic, bidirectional fashion. Therefore, the differential expression of GAD65 and 67 during prolonged changes in neuronal activity may be implicated in some aspects of bidirectional homeostatic plasticity within mature GABAergic presynapses.
authors.affiliation: Tokai University Institute of Innovative Science and Technology, Medical Division, Kanagawa, Japan; School of Medicine, Tokai University, Kanagawa, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hanno-Iijima
authors.affiliation: Tokai University Institute of Innovative Science and Technology, Medical Division, Kanagawa, Japan; School of Medicine, Tokai University, Kanagawa, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Tokai University Institute of Innovative Science and Technology, Medical Division, Kanagawa, Japan; School of Medicine, Tokai University, Kanagawa, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Iijima
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D002070:Butadienes / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004790:Enzyme Induction / Q000187:drug effects; D059330:GABAergic Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005968:Glutamate Decarboxylase / Q000096:biosynthesis* / Q000235:genetics; D006706:Homeostasis; D026121:Indole Alkaloids / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D009570:Nitriles / Q000494:pharmacology; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D001640:Bicuculline; D019208:Brain-Derived Neurotrophic Factor; D002070:Butadienes; D002227:Carbazoles; D005968:Glutamate Decarboxylase; D026121:Indole Alkaloids; D009570:Nitriles; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D020813:Receptor, trkB; D016194:Receptors, N-Methyl-D-Aspartate; D013449:Sulfonamides; D005680:gamma-Aminobutyric Acid; C113580:U 0126; C072105:KN 93; D000096926:Benzenesulfonamides; C049985:staurosporine aglycone; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2