Dystroglycan mediates homeostatic synaptic plasticity at GABAergic synapses

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-05, Vol.111 (18), p.6810-6815
• Main Authors: Pribiag, Horia, Peng, Huashan, Shah, Waris Ali, Stellwagen, David, Carbonetto, Salvatore
• Format: Article
• Language: English
• Subjects: Agrin - metabolism; Animals; Biological Sciences; Brain; Cell adhesion & migration; Dystroglycans; Dystroglycans - antagonists & inhibitors; Dystroglycans - genetics; Dystroglycans - metabolism; Female; GABAergic Neurons - metabolism; Glycosylation; Hippocampus - metabolism; Homeostasis; Humans; Ligands; Male; Mice; Mice, Inbred mdx; MicroRNA; Muscular dystrophies; Muscular Dystrophy, Animal - genetics; Muscular Dystrophy, Animal - metabolism; Mutation; N-Acetylglucosaminyltransferases - antagonists & inhibitors; N-Acetylglucosaminyltransferases - genetics; N-Acetylglucosaminyltransferases - metabolism; Neurology; Neuronal Plasticity - physiology; Neurons; Neuropsychology; Physiological regulation; Protein synthesis; Rats; Rats, Sprague-Dawley; Receptors, GABA-A - metabolism; RNA Interference; RNA, Small Interfering - genetics; RNA-protein interactions; Small interfering RNA; Synapses; Synapses - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1321774111

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 GABA A receptors (GABA ARs), 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 GABA AR 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.