Cargando…

Removal of the Potassium Chloride Co-Transporter from the Somatodendritic Membrane of Axotomized Motoneurons Is Independent of BDNF/TrkB Signaling But Is Controlled by Neuromuscular Innervation

The potassium-chloride cotransporter (KCC2) maintains the low intracellular chloride found in mature central neurons and controls the strength and direction of GABA/glycine synapses. We found that following axotomy as a consequence of peripheral nerve injuries (PNIs), KCC2 protein is lost throughout...

Descripción completa

Detalles Bibliográficos
Autores principales: Akhter, Erica Tracey, Griffith, Ronald W., English, Arthur W., Alvarez, Francisco J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for Neuroscience 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795555/
https://www.ncbi.nlm.nih.gov/pubmed/31541001
http://dx.doi.org/10.1523/ENEURO.0172-19.2019
_version_ 1783459467837308928
author Akhter, Erica Tracey
Griffith, Ronald W.
English, Arthur W.
Alvarez, Francisco J.
author_facet Akhter, Erica Tracey
Griffith, Ronald W.
English, Arthur W.
Alvarez, Francisco J.
author_sort Akhter, Erica Tracey
collection PubMed
description The potassium-chloride cotransporter (KCC2) maintains the low intracellular chloride found in mature central neurons and controls the strength and direction of GABA/glycine synapses. We found that following axotomy as a consequence of peripheral nerve injuries (PNIs), KCC2 protein is lost throughout the somatodendritic membrane of axotomized spinal cord motoneurons after downregulation of kcc2 mRNA expression. This large loss likely depolarizes the reversal potential of GABA/glycine synapses, resulting in GABAergic-driven spontaneous activity in spinal motoneurons similar to previous reports in brainstem motoneurons. We hypothesized that the mechanism inducing KCC2 downregulation in spinal motoneurons following peripheral axotomy might be mediated by microglia or motoneuron release of BDNF and TrkB activation as has been reported on spinal cord dorsal horn neurons after nerve injury, motoneurons after spinal cord injury (SCI), and in many other central neurons throughout development or a variety of pathologies. To test this hypothesis, we used genetic approaches to interfere with microglia activation or delete bdnf from specifically microglia or motoneurons, as well as pharmacology (ANA-12) and pharmacogenetics (F616A mice) to block TrkB activation. We show that KCC2 dysregulation in axotomized motoneurons is independent of microglia, BDNF, and TrkB. KCC2 is instead dependent on neuromuscular innervation; KCC2 levels are restored only when motoneurons reinnervate muscle. Thus, downregulation of KCC2 occurs specifically while injured motoneurons are regenerating and might be controlled by target-derived signals. GABAergic and glycinergic synapses might therefore depolarize motoneurons disconnected from their targets and contribute to augment motoneuron activity known to promote motor axon regeneration.
format Online
Article
Text
id pubmed-6795555
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Society for Neuroscience
record_format MEDLINE/PubMed
spelling pubmed-67955552019-10-17 Removal of the Potassium Chloride Co-Transporter from the Somatodendritic Membrane of Axotomized Motoneurons Is Independent of BDNF/TrkB Signaling But Is Controlled by Neuromuscular Innervation Akhter, Erica Tracey Griffith, Ronald W. English, Arthur W. Alvarez, Francisco J. eNeuro New Research The potassium-chloride cotransporter (KCC2) maintains the low intracellular chloride found in mature central neurons and controls the strength and direction of GABA/glycine synapses. We found that following axotomy as a consequence of peripheral nerve injuries (PNIs), KCC2 protein is lost throughout the somatodendritic membrane of axotomized spinal cord motoneurons after downregulation of kcc2 mRNA expression. This large loss likely depolarizes the reversal potential of GABA/glycine synapses, resulting in GABAergic-driven spontaneous activity in spinal motoneurons similar to previous reports in brainstem motoneurons. We hypothesized that the mechanism inducing KCC2 downregulation in spinal motoneurons following peripheral axotomy might be mediated by microglia or motoneuron release of BDNF and TrkB activation as has been reported on spinal cord dorsal horn neurons after nerve injury, motoneurons after spinal cord injury (SCI), and in many other central neurons throughout development or a variety of pathologies. To test this hypothesis, we used genetic approaches to interfere with microglia activation or delete bdnf from specifically microglia or motoneurons, as well as pharmacology (ANA-12) and pharmacogenetics (F616A mice) to block TrkB activation. We show that KCC2 dysregulation in axotomized motoneurons is independent of microglia, BDNF, and TrkB. KCC2 is instead dependent on neuromuscular innervation; KCC2 levels are restored only when motoneurons reinnervate muscle. Thus, downregulation of KCC2 occurs specifically while injured motoneurons are regenerating and might be controlled by target-derived signals. GABAergic and glycinergic synapses might therefore depolarize motoneurons disconnected from their targets and contribute to augment motoneuron activity known to promote motor axon regeneration. Society for Neuroscience 2019-10-15 /pmc/articles/PMC6795555/ /pubmed/31541001 http://dx.doi.org/10.1523/ENEURO.0172-19.2019 Text en Copyright © 2019 Akhter et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle New Research
Akhter, Erica Tracey
Griffith, Ronald W.
English, Arthur W.
Alvarez, Francisco J.
Removal of the Potassium Chloride Co-Transporter from the Somatodendritic Membrane of Axotomized Motoneurons Is Independent of BDNF/TrkB Signaling But Is Controlled by Neuromuscular Innervation
title Removal of the Potassium Chloride Co-Transporter from the Somatodendritic Membrane of Axotomized Motoneurons Is Independent of BDNF/TrkB Signaling But Is Controlled by Neuromuscular Innervation
title_full Removal of the Potassium Chloride Co-Transporter from the Somatodendritic Membrane of Axotomized Motoneurons Is Independent of BDNF/TrkB Signaling But Is Controlled by Neuromuscular Innervation
title_fullStr Removal of the Potassium Chloride Co-Transporter from the Somatodendritic Membrane of Axotomized Motoneurons Is Independent of BDNF/TrkB Signaling But Is Controlled by Neuromuscular Innervation
title_full_unstemmed Removal of the Potassium Chloride Co-Transporter from the Somatodendritic Membrane of Axotomized Motoneurons Is Independent of BDNF/TrkB Signaling But Is Controlled by Neuromuscular Innervation
title_short Removal of the Potassium Chloride Co-Transporter from the Somatodendritic Membrane of Axotomized Motoneurons Is Independent of BDNF/TrkB Signaling But Is Controlled by Neuromuscular Innervation
title_sort removal of the potassium chloride co-transporter from the somatodendritic membrane of axotomized motoneurons is independent of bdnf/trkb signaling but is controlled by neuromuscular innervation
topic New Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795555/
https://www.ncbi.nlm.nih.gov/pubmed/31541001
http://dx.doi.org/10.1523/ENEURO.0172-19.2019
work_keys_str_mv AT akhterericatracey removalofthepotassiumchloridecotransporterfromthesomatodendriticmembraneofaxotomizedmotoneuronsisindependentofbdnftrkbsignalingbutiscontrolledbyneuromuscularinnervation
AT griffithronaldw removalofthepotassiumchloridecotransporterfromthesomatodendriticmembraneofaxotomizedmotoneuronsisindependentofbdnftrkbsignalingbutiscontrolledbyneuromuscularinnervation
AT englisharthurw removalofthepotassiumchloridecotransporterfromthesomatodendriticmembraneofaxotomizedmotoneuronsisindependentofbdnftrkbsignalingbutiscontrolledbyneuromuscularinnervation
AT alvarezfranciscoj removalofthepotassiumchloridecotransporterfromthesomatodendriticmembraneofaxotomizedmotoneuronsisindependentofbdnftrkbsignalingbutiscontrolledbyneuromuscularinnervation