α6-Containing GABAA Receptors Are the Principal Mediators of Inhibitory Synapse Strengthening by Insulin in Cerebellar Granule Cells
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. H...
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| Veröffentlicht in: | The Journal of neuroscience 2015-07, Vol.35 (26), p.9676-9688 |
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| creator | Accardi, Michael V Brown, Patricia M G E Miraucourt, Loïs S Orser, Beverley A Bowie, Derek |
| description | 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. |
| doi_str_mv | 10.1523/JNEUROSCI.0513-15.2015 |
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Brown, Patricia M G E ; Miraucourt, Loïs S ; Orser, Beverley A ; Bowie, Derek</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p266t-61b7b19507c0430d8e58eb3f536c85b00f19099f99a331ee1bd5ea30eee8e1c33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>2-Amino-5-phosphonovalerate - pharmacology</topic><topic>6-Cyano-7-nitroquinoxaline-2,3-dione - pharmacology</topic><topic>Animals</topic><topic>Animals, Newborn</topic><topic>Cerebellum - cytology</topic><topic>Excitatory Amino Acid Antagonists - pharmacology</topic><topic>Furosemide - pharmacology</topic><topic>gamma-Aminobutyric Acid - pharmacology</topic><topic>Hypoglycemic Agents - pharmacology</topic><topic>In Vitro Techniques</topic><topic>Inhibitory Postsynaptic Potentials - drug effects</topic><topic>Inhibitory Postsynaptic Potentials - genetics</topic><topic>Insulin - pharmacology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Neurons - drug effects</topic><topic>Protein Subunits - genetics</topic><topic>Protein Subunits - metabolism</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Receptors, GABA-A - genetics</topic><topic>Receptors, GABA-A - metabolism</topic><topic>Sodium Potassium Chloride Symporter Inhibitors - pharmacology</topic><topic>Synapses - drug effects</topic><topic>Synapses - genetics</topic><topic>Synaptic Transmission - drug effects</topic><topic>Synaptic Transmission - genetics</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Accardi, Michael V</creatorcontrib><creatorcontrib>Brown, Patricia M G E</creatorcontrib><creatorcontrib>Miraucourt, Loïs S</creatorcontrib><creatorcontrib>Orser, Beverley A</creatorcontrib><creatorcontrib>Bowie, Derek</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Accardi, Michael V</au><au>Brown, Patricia M G E</au><au>Miraucourt, Loïs S</au><au>Orser, Beverley A</au><au>Bowie, Derek</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>α6-Containing GABAA Receptors Are the Principal Mediators of Inhibitory Synapse Strengthening by Insulin in Cerebellar Granule Cells</atitle><jtitle>The Journal of neuroscience</jtitle><addtitle>J Neurosci</addtitle><date>2015-07-01</date><risdate>2015</risdate><volume>35</volume><issue>26</issue><spage>9676</spage><epage>9688</epage><pages>9676-9688</pages><issn>0270-6474</issn><eissn>1529-2401</eissn><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. 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| subjects | 2-Amino-5-phosphonovalerate - pharmacology 6-Cyano-7-nitroquinoxaline-2,3-dione - pharmacology Animals Animals, Newborn Cerebellum - cytology Excitatory Amino Acid Antagonists - pharmacology Furosemide - pharmacology gamma-Aminobutyric Acid - pharmacology Hypoglycemic Agents - pharmacology In Vitro Techniques Inhibitory Postsynaptic Potentials - drug effects Inhibitory Postsynaptic Potentials - genetics Insulin - pharmacology Mice Mice, Inbred C57BL Mice, Knockout Neurons - drug effects Protein Subunits - genetics Protein Subunits - metabolism Reactive Oxygen Species - metabolism Receptors, GABA-A - genetics Receptors, GABA-A - metabolism Sodium Potassium Chloride Symporter Inhibitors - pharmacology Synapses - drug effects Synapses - genetics Synaptic Transmission - drug effects Synaptic Transmission - genetics Time Factors |
| title | α6-Containing GABAA Receptors Are the Principal Mediators of Inhibitory Synapse Strengthening by Insulin in Cerebellar Granule Cells |
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