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Identification of a molecular locus for normalizing dysregulated GABA release from interneurons in the Fragile X brain.
Yang, Yi-Mei; Arsenault, Jason; Bah, Alaji; Krzeminski, Mickael; Fekete, Adam; Chao, Owen Y; Pacey, Laura K; Wang, Alex; Forman-Kay, Julie; Hampson, David R; Wang, Lu-Yang.
Afiliación
  • Yang YM; Department of Biomedical Sciences, University of Minnesota Medical School, 1035 University Drive, Duluth, MN, 55812, USA. ymyang@d.umn.edu.
  • Arsenault J; Program in Neurosciences & Mental Health, SickKids Research Institute, Toronto, ON, M5G 1X8, Canada. ymyang@d.umn.edu.
  • Bah A; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Canada. ymyang@d.umn.edu.
  • Krzeminski M; Program in Neurosciences & Mental Health, SickKids Research Institute, Toronto, ON, M5G 1X8, Canada.
  • Fekete A; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Canada.
  • Chao OY; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada.
  • Pacey LK; Program in Molecular Medicine, SickKids Research Institute, Toronto, ON, M5G 1X8, Canada.
  • Wang A; Program in Molecular Medicine, SickKids Research Institute, Toronto, ON, M5G 1X8, Canada.
  • Forman-Kay J; Program in Neurosciences & Mental Health, SickKids Research Institute, Toronto, ON, M5G 1X8, Canada.
  • Hampson DR; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Canada.
  • Wang LY; Department of Biomedical Sciences, University of Minnesota Medical School, 1035 University Drive, Duluth, MN, 55812, USA.
Mol Psychiatry ; 25(9): 2017-2035, 2020 09.
Article en En | MEDLINE | ID: mdl-30224722
Principal neurons encode information by varying their firing rate and patterns precisely fine-tuned through GABAergic interneurons. Dysregulation of inhibition can lead to neuropsychiatric disorders, yet little is known about the molecular basis underlying inhibitory control. Here, we find that excessive GABA release from basket cells (BCs) attenuates the firing frequency of Purkinje neurons (PNs) in the cerebellum of Fragile X Mental Retardation 1 (Fmr1) knockout (KO) mice, a model of Fragile X Syndrome (FXS) with abrogated expression of the Fragile X Mental Retardation Protein (FMRP). This over-inhibition originates from increased excitability and Ca2+ transients in the presynaptic terminals, where Kv1.2 potassium channels are downregulated. By paired patch-clamp recordings, we further demonstrate that acutely introducing an N-terminal fragment of FMRP into BCs normalizes GABA release in the Fmr1-KO synapses. Conversely, direct injection of an inhibitory FMRP antibody into BCs, or membrane depolarization of BCs, enhances GABA release in the wild type synapses, leading to abnormal inhibitory transmission comparable to the Fmr1-KO neurons. We discover that the N-terminus of FMRP directly binds to a phosphorylated serine motif on the C-terminus of Kv1.2; and that loss of this interaction in BCs exaggerates GABA release, compromising the firing activity of PNs and thus the output from the cerebellar circuitry. An allosteric Kv1.2 agonist, docosahexaenoic acid, rectifies the dysregulated inhibition in vitro as well as acoustic startle reflex and social interaction in vivo of the Fmr1-KO mice. Our results unravel a novel molecular locus for targeted intervention of FXS and perhaps autism.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil / Síndrome del Cromosoma X Frágil Tipo de estudio: Diagnostic_studies Límite: Animals Idioma: En Revista: Mol Psychiatry Asunto de la revista: BIOLOGIA MOLECULAR / PSIQUIATRIA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil / Síndrome del Cromosoma X Frágil Tipo de estudio: Diagnostic_studies Límite: Animals Idioma: En Revista: Mol Psychiatry Asunto de la revista: BIOLOGIA MOLECULAR / PSIQUIATRIA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido