title: Dystroglycan mediates homeostatic synaptic plasticity at GABAergic synapses.
abstract: Dystroglycan (DG), a cell adhesion molecule well known to be essential for skeletal muscle integrity and formation of neuromuscular synapses, is also present at inhibitory synapses in the central nervous system. Mutations that affect DG function not only result in muscular dystrophies, but also in severe cognitive deficits and epilepsy. Here we demonstrate a role of DG during activity-dependent homeostatic regulation of hippocampal inhibitory synapses. Prolonged elevation of neuronal activity up-regulates DG expression and glycosylation, and its localization to inhibitory synapses. Inhibition of protein synthesis prevents the activity-dependent increase in synaptic DG and GABAA receptors (GABAARs), as well as the homeostatic scaling up of GABAergic synaptic transmission. RNAi-mediated knockdown of DG blocks homeostatic scaling up of inhibitory synaptic strength, as does knockdown of like-acetylglucosaminyltransferase (LARGE)--a glycosyltransferase critical for DG function. In contrast, DG is not required for the bicuculline-induced scaling down of excitatory synaptic strength or the tetrodotoxin-induced scaling down of inhibitory synaptic strength. The DG ligand agrin increases GABAergic synaptic strength in a DG-dependent manner that mimics homeostatic scaling up induced by increased activity, indicating that activation of this pathway alone is sufficient to regulate GABAAR trafficking. These data demonstrate that DG is regulated in a physiologically relevant manner in neurons and that DG and its glycosylation are essential for homeostatic plasticity at inhibitory synapses.
authors.affiliation: Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, Research Institute of McGill University Health Center, Montréal, QC, Canada H3G 1A4.
authors.forename: Horia
authors.initials: H
authors.lastname: Pribiag
authors.forename: Huashan
authors.initials: H
authors.lastname: Peng
authors.forename: Waris Ali
authors.initials: WA
authors.lastname: Shah
authors.forename: David
authors.initials: D
authors.lastname: Stellwagen
authors.forename: Salvatore
authors.initials: S
authors.lastname: Carbonetto
mesh_terms: D018171:Agrin / Q000378:metabolism; D000818:Animals; D049030:Dystroglycans / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism*; D006031:Glycosylation; D006624:Hippocampus / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D013569:Synapses / Q000378:metabolism
chemical_list: D018171:Agrin; D034741:RNA, Small Interfering; D011963:Receptors, GABA-A; D049030:Dystroglycans; D017351:N-Acetylglucosaminyltransferases
keywords: AMPA receptors; dystrophin; excitation–inhibition balance; muscular dystrophy; retardation
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