Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy

Nature Neuroscience
Emily V FletcherGeorge Z Mentis

Abstract

Behavioral deficits in neurodegenerative diseases are often attributed to the selective dysfunction of vulnerable neurons via cell-autonomous mechanisms. Although vulnerable neurons are embedded in neuronal circuits, the contributions of their synaptic partners to disease process are largely unknown. Here we show that, in a mouse model of spinal muscular atrophy (SMA), a reduction in proprioceptive synaptic drive leads to motor neuron dysfunction and motor behavior impairments. In SMA mice or after the blockade of proprioceptive synaptic transmission, we observed a decrease in the motor neuron firing that could be explained by the reduction in the expression of the potassium channel Kv2.1 at the surface of motor neurons. Chronically increasing neuronal activity pharmacologically in vivo led to a normalization of Kv2.1 expression and an improvement in motor function. Our results demonstrate a key role of excitatory synaptic drive in shaping the function of motor neurons during development and the contribution of its disruption to a neurodegenerative disease.

References

Jan 1, 1979·Progress in Neurobiology·S Redman
Aug 31, 1977·Experimental Brain Research·J Altman, S A Bayer
Aug 1, 1983·Journal of Neurophysiology·A Lev-TovW Rall
Aug 1, 1982·The Journal of Physiology·C J De LucaA P Xenakis
Jan 1, 1995·Advances in Experimental Medicine and Biology·C K Thomas
May 1, 1997·Brain Research. Brain Research Protocols·M Isokawa
Jun 29, 2001·Reviews of Physiology, Biochemistry and Pharmacology·R K Powers, M D Binder
Feb 21, 2003·Current Opinion in Neurobiology·Hsiao-Huei ChenEric Frank
Oct 3, 2003·Journal of Neurophysiology·Jason J KuoAlfons B A Kroese
Apr 6, 2004·The Journal of Comparative Neurology·Francisco J AlvarezStephen P Schneider
Jun 15, 2004·Nature Neuroscience·Hiroaki MisonouJames S Trimmer
Apr 17, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Neil A ShneiderMichael J O'Donovan
Jun 11, 2009·Journal of Child Neurology·Jacqueline MontesPetra Kaufmann
Feb 9, 2010·Current Opinion in Neurobiology·Lidia Garcia-CampmanyMartyn Goulding
Feb 20, 2010·The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology·Bettina HesseNadja Schilling
Nov 27, 2010·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Adam Bleckert, Rachel O L Wong
Jul 26, 2011·The Journal of Clinical Investigation·Cathleen M LutzUmrao R Monani
Mar 17, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Rocky G GogliottiChristine J Didonato
Jun 23, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Tara L MartinezCharlotte J Sumner
Jun 27, 2012·Nature Reviews. Neurology·Rosa RademakersIan R Mackenzie
Oct 16, 2012·Cell·Francesco LottiLivio Pellizzoni
Mar 7, 2014·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Travis M RottermanFrancisco J Alvarez
Apr 4, 2014·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Pin W Liu, Bruce P Bean
May 9, 2014·Journal of Neurophysiology·Laura K RitterVicki M Tysseling
Jul 22, 2014·Journal of Biomechanics·Derek P ZwambagStephen H M Brown
Aug 30, 2014·Neuroreport·Jong-Keun LeeIk-Hwan Kim
Jun 13, 2015·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Sarah Tisdale, Livio Pellizzoni
Jun 23, 2015·Neuron·Alana I MendelsohnThomas M Jessell

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Citations

Dec 12, 2017·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Fumiyasu Imai, Yutaka Yoshida
Feb 10, 2018·Nature Reviews. Neurology·Ewout J N GroenThomas H Gillingwater
Nov 25, 2017·Annals of Neurology·Paul NardelliMark M Rich
Sep 21, 2017·Frontiers in Cellular Neuroscience·Saravanan ArumugamLucía Tabares
Oct 3, 2019·Scientific Reports·Filipe NascimentoGareth B Miles
May 31, 2019·The Journal of Physiology·Shannon H RomerRobert E W Fyffe
Feb 8, 2020·Journal of Cachexia, Sarcopenia and Muscle·Haiyan ZhouFrancesco Muntoni
Nov 5, 2019·The European Journal of Neuroscience·Marcin BączykPiotr Krutki
Jun 3, 2020·The Journal of Experimental Medicine·Marcin BączykDaniel Zytnicki
May 24, 2019·Science Translational Medicine·Elizabeth M C Fisher, David M Bannerman
May 11, 2020·Journal of Neurology·Fabrício Castro de BorbaPierre-François Pradat
May 26, 2020·Neuroscience Bulletin·Yongjie Wang, Zhihui Huang
Sep 22, 2018·Brain : a Journal of Neurology·Hannah K ShorrockThomas H Gillingwater
Jul 7, 2018·Child Neurology Open·Christina StarkEckhard Schoenau
Mar 20, 2019·Frontiers in Molecular Neuroscience·Hannah K ShorrockEwout J N Groen
Jun 12, 2020·Frontiers in Molecular Neuroscience·Mélanie Falgairolle, Michael J O'Donovan
Jan 16, 2021·The Journal of Physiology·Adam S DeardorffRobert E W Fyffe
Feb 2, 2021·Neurology. Clinical Practice·Maryam OskouiDarryl C De Vivo
Jan 29, 2021·Science Translational Medicine·Lingling KongCharlotte J Sumner
Mar 2, 2021·Neural Regeneration Research·Kishore GollapalliUmrao R Monani
Aug 14, 2020·Neuromuscular Disorders : NMD·Claudia A ChiribogaBrian McCabe
Apr 3, 2021·Nature Neuroscience·Meaghan Van AlstyneLivio Pellizzoni
May 2, 2021·Proceedings of the National Academy of Sciences of the United States of America·Niko HenselPeter Claus
May 23, 2021·Pflügers Archiv : European journal of physiology·Vladimir A Martínez-RojasCarlo Musio
Jun 15, 2021·EMBO Molecular Medicine·Alberto CataneseTobias M Böckers
Jun 17, 2021·Nature Neuroscience·Richard S Finkel, Kenneth H Fischbeck
Jul 6, 2021·Current Opinion in Physiology·Jennifer L ShadrachJulia A Kaltschmidt
May 18, 2021·Journal of Neural Transmission·Federica FulceriFrancesco Fornai
Jul 13, 2021·Frontiers in Cellular Neuroscience·Andres Di PaoloJosé Roberto Sotelo-Silveira
Jul 20, 2021·Journal of Chemical Neuroanatomy·Ting DingDonald W Pfaff
Aug 21, 2021·Nature Communications·Giulietta M RiboldiFrancesco Lotti

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Datasets Mentioned

BETA
AB10672253

Methods Mentioned

BETA
SMA
targeted
transgenic
targeted mutation
PCR
genotyping
dissection
Fluorescence

Key Resources (RRID) Mentioned

AB10672253
AB_2315869

Software Mentioned

Leica LAS AF
LAS X
Excel
LASAF
Leica
pClamp
Clampfit

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