title: GABAergic inhibition regulates developmental synapse elimination in the cerebellum.
abstract: Functional neural circuit formation during development involves massive elimination of redundant synapses. In the cerebellum, one-to-one connection from excitatory climbing fiber (CF) to Purkinje cell (PC) is established by elimination of early-formed surplus CFs. This process depends on glutamatergic excitatory inputs, but contribution of GABAergic transmission remains unclear. Here, we demonstrate impaired CF synapse elimination in mouse models with diminished GABAergic transmission by mutation of a single allele for the GABA synthesizing enzyme GAD67, by conditional deletion of GAD67 from PCs and GABAergic interneurons or by pharmacological inhibition of cerebellar GAD activity. The impaired CF synapse elimination was rescued by enhancing GABA(A) receptor sensitivity in the cerebellum by locally applied diazepam. Our electrophysiological and Ca2+ imaging data suggest that GABA(A) receptor-mediated inhibition onto the PC soma from molecular layer interneurons influences CF-induced Ca2+ transients in the soma and regulates CF synapse elimination from postnatal day 10 (P10) to around P16.
authors.affiliation: Department of Neurophysiology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Nakayama
authors.forename: Taisuke
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kitamura
authors.forename: Kouichi
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Yuchio
authors.initials: Y
authors.lastname: Yanagawa
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Obata
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakimura
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kano
mesh_terms: D060848:Agatoxins / Q000494:pharmacology; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000494:pharmacology; D055592:Biophysical Phenomena / Q000187:drug effects / Q000235:genetics; D001703:Biophysics; D064026:Calbindins; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology* / Q000254:growth & development*; D002867:Chromones / Q000494:pharmacology; D045304:Cytochromes c / Q000494:pharmacology; D003712:Dendrites / Q000648:ultrastructure; D003975:Diazepam / Q000494:pharmacology; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D018757:GABA Modulators / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology; D005968:Glutamate Decarboxylase / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D054799:Phospholipase C beta / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011689:Purkinje Cells / Q000166:cytology* / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology; D017470:Receptors, Glutamate / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C117789:7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester; D060848:Agatoxins; D064026:Calbindins; D015220:Calcium Channels; D002867:Chromones; D018691:Excitatory Amino Acid Antagonists; D018757:GABA Modulators; D058787:GABA-A Receptor Antagonists; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D011810:Quinoxalines; D017470:Receptors, Glutamate; D018094:Receptors, Metabotropic Glutamate; D064030:S100 Calcium Binding Protein G; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; C485184:enhanced green fluorescent protein; C107913:glutamate receptor delta 2; C104077:metabotropic glutamate receptor type 1; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D049452:Green Fluorescent Proteins; D005680:gamma-Aminobutyric Acid; D045304:Cytochromes c; D011493:Protein Kinase C; D054799:Phospholipase C beta; C518043:Plcb4 protein, mouse; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D003975:Diazepam; D002118:Calcium; D001640:Bicuculline