title: α6-Containing GABAA Receptors Are the Principal Mediators of Inhibitory Synapse Strengthening by Insulin in Cerebellar Granule Cells.
abstract: Activity-dependent strengthening of central synapses is a key factor driving neuronal circuit behavior in the vertebrate CNS. At fast inhibitory synapses, strengthening is thought to occur by increasing the number of GABAA receptors (GABARs) of the same subunit composition to preexisting synapses. Here, we show that strengthening of mouse cerebellar granule cell GABAergic synapses occurs by a different mechanism. Specifically, we show that the neuropeptide hormone, insulin, strengthens inhibitory synapses by recruiting α6-containing GABARs rather than accumulating more α1-containing receptors that are resident to the synapse. Because α6-receptors are targeted to functionally distinct postsynaptic sites from α1-receptors, we conclude that only a subset of all inhibitory synapses are strengthened. Together with our recent findings on stellate cells, we propose a general mechanism by which mature inhibitory synapses are strengthened. In this scenario, α1-GABARs resident to inhibitory synapses form the hardwiring of neuronal circuits with receptors of a different composition fulfilling a fundamental, but unappreciated, role in synapse strengthening.
authors.affiliation: Department of Pharmacology and Therapeutics, Graduate Program in Pharmacology, and.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Accardi
authors.affiliation: Department of Pharmacology and Therapeutics, Integrated Program in Neuroscience, McGill University, Montréal, Québec H3A 2B4, Canada, and.
authors.forename: Patricia M G E
authors.initials: PM
authors.lastname: Brown
authors.affiliation: Department of Pharmacology and Therapeutics.
authors.forename: Loïs S
authors.initials: LS
authors.lastname: Miraucourt
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Beverley A
authors.initials: BA
authors.lastname: Orser
authors.affiliation: Department of Pharmacology and Therapeutics, derek.bowie@mcgill.ca.
authors.forename: Derek
authors.identifier: http://orcid.org/0000-0001-9491-8768
authors.initials: D
authors.lastname: Bowie
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002531:Cerebellum / Q000166:cytology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005665:Furosemide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects* / Q000235:genetics; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000235:genetics; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D018691:Excitatory Amino Acid Antagonists; C583130:Gabrd protein, mouse; D007004:Hypoglycemic Agents; D007328:Insulin; D021122:Protein Subunits; D017382:Reactive Oxygen Species; D011963:Receptors, GABA-A; D049994:Sodium Potassium Chloride Symporter Inhibitors; D005680:gamma-Aminobutyric Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; D005665:Furosemide
keywords: inhibition; insulin; metabolism; mitochondria; plasticity mechanism; reactive oxygen species