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Facilitation of GluN2C-containing NMDA receptors in the external globus pallidus increases firing of fast spiking neurons and improves motor function in a hemiparkinsonian mouse model
Globus pallidus externa (GPe) is a nucleus in the basal ganglia circuitry involved in the control of movement. Recent studies have demonstrated a critical role of GPe cell types in Parkinsonism. Specifically increasing the function of parvalbumin (PV) neurons in the GPe has been found to facilitate...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063913/ https://www.ncbi.nlm.nih.gov/pubmed/33421565 http://dx.doi.org/10.1016/j.nbd.2021.105254 |
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author | Liu, Jinxu Shelkar, Gajanan P. Sarode, Lopmudra P. Gawande, Dinesh Y. Zhao, Fabao Clausen, Rasmus Praetorius Ugale, Rajesh R. Dravid, Shashank Manohar |
author_facet | Liu, Jinxu Shelkar, Gajanan P. Sarode, Lopmudra P. Gawande, Dinesh Y. Zhao, Fabao Clausen, Rasmus Praetorius Ugale, Rajesh R. Dravid, Shashank Manohar |
author_sort | Liu, Jinxu |
collection | PubMed |
description | Globus pallidus externa (GPe) is a nucleus in the basal ganglia circuitry involved in the control of movement. Recent studies have demonstrated a critical role of GPe cell types in Parkinsonism. Specifically increasing the function of parvalbumin (PV) neurons in the GPe has been found to facilitate motor function in a mouse model of Parkinson’s disease (PD). The knowledge of contribution of NMDA receptors to GPe function is limited. Here, we demonstrate that fast spiking neurons in the GPe express NMDA receptor currents sensitive to GluN2C/GluN2D-selective inhibitors and glycine site agonist with higher efficacy at GluN2C-containing receptors. Furthermore, using a novel reporter model, we demonstrate the expression of GluN2C subunits in PV neurons in the GPe which project to subthalamic nuclei. GluN2D subunit was also found to localize to PV neurons in GPe. Ablation of GluN2C subunit does not affect spontaneous firing of fast spiking neurons. In contrast, facilitating the function of GluN2C-containing receptors using glycine-site NMDA receptor agonists, D-cycloserine (DCS) or AICP, increased the spontaneous firing frequency of PV neurons in a GluN2C-dependent manner. Finally, we demonstrate that local infusion of DCS or AICP into the GPe improved motor function in a mouse model of PD. Together, these results demonstrate that GluN2C-containing receptors and potentially GluN2D-containing receptors in the GPe may serve as a therapeutic target for alleviating motor dysfunction in PD and related disorders. |
format | Online Article Text |
id | pubmed-8063913 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
record_format | MEDLINE/PubMed |
spelling | pubmed-80639132021-04-23 Facilitation of GluN2C-containing NMDA receptors in the external globus pallidus increases firing of fast spiking neurons and improves motor function in a hemiparkinsonian mouse model Liu, Jinxu Shelkar, Gajanan P. Sarode, Lopmudra P. Gawande, Dinesh Y. Zhao, Fabao Clausen, Rasmus Praetorius Ugale, Rajesh R. Dravid, Shashank Manohar Neurobiol Dis Article Globus pallidus externa (GPe) is a nucleus in the basal ganglia circuitry involved in the control of movement. Recent studies have demonstrated a critical role of GPe cell types in Parkinsonism. Specifically increasing the function of parvalbumin (PV) neurons in the GPe has been found to facilitate motor function in a mouse model of Parkinson’s disease (PD). The knowledge of contribution of NMDA receptors to GPe function is limited. Here, we demonstrate that fast spiking neurons in the GPe express NMDA receptor currents sensitive to GluN2C/GluN2D-selective inhibitors and glycine site agonist with higher efficacy at GluN2C-containing receptors. Furthermore, using a novel reporter model, we demonstrate the expression of GluN2C subunits in PV neurons in the GPe which project to subthalamic nuclei. GluN2D subunit was also found to localize to PV neurons in GPe. Ablation of GluN2C subunit does not affect spontaneous firing of fast spiking neurons. In contrast, facilitating the function of GluN2C-containing receptors using glycine-site NMDA receptor agonists, D-cycloserine (DCS) or AICP, increased the spontaneous firing frequency of PV neurons in a GluN2C-dependent manner. Finally, we demonstrate that local infusion of DCS or AICP into the GPe improved motor function in a mouse model of PD. Together, these results demonstrate that GluN2C-containing receptors and potentially GluN2D-containing receptors in the GPe may serve as a therapeutic target for alleviating motor dysfunction in PD and related disorders. 2021-01-06 2021-03 /pmc/articles/PMC8063913/ /pubmed/33421565 http://dx.doi.org/10.1016/j.nbd.2021.105254 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license, (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ). |
spellingShingle | Article Liu, Jinxu Shelkar, Gajanan P. Sarode, Lopmudra P. Gawande, Dinesh Y. Zhao, Fabao Clausen, Rasmus Praetorius Ugale, Rajesh R. Dravid, Shashank Manohar Facilitation of GluN2C-containing NMDA receptors in the external globus pallidus increases firing of fast spiking neurons and improves motor function in a hemiparkinsonian mouse model |
title | Facilitation of GluN2C-containing NMDA receptors in the external globus pallidus increases firing of fast spiking neurons and improves motor function in a hemiparkinsonian mouse model |
title_full | Facilitation of GluN2C-containing NMDA receptors in the external globus pallidus increases firing of fast spiking neurons and improves motor function in a hemiparkinsonian mouse model |
title_fullStr | Facilitation of GluN2C-containing NMDA receptors in the external globus pallidus increases firing of fast spiking neurons and improves motor function in a hemiparkinsonian mouse model |
title_full_unstemmed | Facilitation of GluN2C-containing NMDA receptors in the external globus pallidus increases firing of fast spiking neurons and improves motor function in a hemiparkinsonian mouse model |
title_short | Facilitation of GluN2C-containing NMDA receptors in the external globus pallidus increases firing of fast spiking neurons and improves motor function in a hemiparkinsonian mouse model |
title_sort | facilitation of glun2c-containing nmda receptors in the external globus pallidus increases firing of fast spiking neurons and improves motor function in a hemiparkinsonian mouse model |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063913/ https://www.ncbi.nlm.nih.gov/pubmed/33421565 http://dx.doi.org/10.1016/j.nbd.2021.105254 |
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