title: AMPA receptor-mediated presynaptic inhibition at cerebellar GABAergic synapses: a characterization of molecular mechanisms.
abstract: A major subtype of glutamate receptors, AMPA receptors (AMPARs), are generally thought to mediate excitation at mammalian central synapses via the ionotropic action of ligand-gated channel opening. It has recently emerged, however, that synaptic activation of AMPARs by glutamate released from the climbing fibre input elicits not only postsynaptic excitation but also presynaptic inhibition of GABAergic transmission onto Purkinje cells in the cerebellar cortex. Although presynaptic inhibition is critical for information processing at central synapses, the molecular mechanisms by which AMPARs take part in such actions are not known. This study therefore aimed at further examining the properties of AMPAR-mediated presynaptic inhibition at GABAergic synapses in the rat cerebellum. Our data provide evidence that the climbing fibre-induced inhibition of GABA release from interneurons depends on AMPAR-mediated activation of GTP-binding proteins coupled with down-regulation of presynaptic voltage-dependent Ca(2+) channels. A G(i/o)-protein inhibitor, N-ethylmaleimide, selectively abolished the AMPAR-mediated presynaptic inhibition at cerebellar GABAergic synapses but did not affect AMPAR-mediated excitatory actions on Purkinje cells. Furthermore, both G(i/o)-coupled receptor agonists, baclofen and DCG-IV, and the P/Q-type calcium channel blocker omega-agatoxin IVA markedly occluded the AMPAR-mediated inhibition of GABAergic transmission. Conversely, AMPAR activation inhibited action potential-triggered Ca(2+) influx into individual axonal boutons of cerebellar GABAergic interneurons. By suppressing the inhibitory inputs to Purkinje cells, the AMPAR-mediated presynaptic inhibition could thus provide a feed-forward mechanism for the information flow from the cerebellar cortex.
authors.affiliation: Laboratory of Molecular Neurobiology, Mitsubishi Kagaku Institute of Life Sciences, and CREST, JST (Japan Science and Technology Corporation), 11 Minamiooya, Machida-shi, Tokyo 194-8511, Japan.
authors.forename: Shin'Ichiro
authors.initials: S
authors.lastname: Satake
authors.forename: Fumihito
authors.initials: F
authors.lastname: Saitow
authors.forename: Dmitri
authors.initials: D
authors.lastname: Rusakov
authors.forename: Shiro
authors.initials: S
authors.lastname: Konishi
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001581:Benzothiadiazines / Q000494:pharmacology; D048588:Benzoxazines; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002531:Cerebellum / Q000166:cytology*; D002614:Chelating Agents / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003521:Cyclopropanes / Q000494:pharmacology; D004347:Drug Interactions; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000187:drug effects / Q000502:physiology*; D012433:Ryanodine / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C095804:(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; D001581:Benzothiadiazines; D048588:Benzoxazines; D002121:Calcium Channel Blockers; D002614:Chelating Agents; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D018091:Receptors, AMPA; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; C474696:methyl-(4-carboxyphenyl)glycine; C082313:2-(2,3-dicarboxycyclopropyl)glycine; D012433:Ryanodine; D005576:Colforsin; C103505:AM 251; D004533:Egtazic Acid; D005680:gamma-Aminobutyric Acid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; C004639:cyclothiazide; D002118:Calcium; D005998:Glycine