Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling

Autores
Lemos, Julia C.; Friend, Danielle M.; Kaplan, Alanna R.; Shin, Jung Hoon; Rubinstein, Marcelo; Kravitz, Alexxai V.; Alvarez, Veronica A.
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Bradykinesia is a prominent phenotype of Parkinson's disease, depression, and other neurological conditions. Disruption of dopamine (DA) transmission plays an important role, but progress in understanding the exact mechanisms driving slowness of movement has been impeded due to the heterogeneity of DA receptor distribution on multiple cell types within the striatum. Here we show that selective deletion of DA D2 receptors (D2Rs) from indirect-pathway medium spiny neurons (iMSNs) is sufficient to impair locomotor activity, phenocopying DA depletion models of Parkinson's disease, despite this mouse model having intact DA transmission. There was a robust enhancement of GABAergic transmission and a reduction of in vivo firing in striatal and pallidal neurons. Mimicking D2R signaling in iMSNs with Gi-DREADDs restored the level of tonic GABAergic transmission and rescued the motor deficit. These findings indicate that DA, through D2R activation in iMSNs, regulates motor output by constraining the strength of GABAergic transmission. Lemos et al. find that targeted deletion of dopamine D2 receptors from indirect-pathway medium spiny neurons (iMSNs) leads to enhanced GABAergic transmission downstream of iMSNs. This enhanced GABAergic tone causes a Parkinsonian-like motor deficit similar to dopamine depletion models.
Fil: Lemos, Julia C.. National Institutes of Health; Estados Unidos
Fil: Friend, Danielle M.. National Institutes of Health; Estados Unidos
Fil: Kaplan, Alanna R.. National Institutes of Health; Estados Unidos
Fil: Shin, Jung Hoon. National Institutes of Health; Estados Unidos
Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Kravitz, Alexxai V.. National Institutes of Health; Estados Unidos
Fil: Alvarez, Veronica A.. National Institutes of Health; Estados Unidos
Materia
Dopamina
Parkinson
Receptor D2
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/39463
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/39463
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor SignalingLemos, Julia C.Friend, Danielle M.Kaplan, Alanna R.Shin, Jung HoonRubinstein, MarceloKravitz, Alexxai V.Alvarez, Veronica A.DopaminaParkinsonReceptor D2https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Bradykinesia is a prominent phenotype of Parkinson's disease, depression, and other neurological conditions. Disruption of dopamine (DA) transmission plays an important role, but progress in understanding the exact mechanisms driving slowness of movement has been impeded due to the heterogeneity of DA receptor distribution on multiple cell types within the striatum. Here we show that selective deletion of DA D2 receptors (D2Rs) from indirect-pathway medium spiny neurons (iMSNs) is sufficient to impair locomotor activity, phenocopying DA depletion models of Parkinson's disease, despite this mouse model having intact DA transmission. There was a robust enhancement of GABAergic transmission and a reduction of in vivo firing in striatal and pallidal neurons. Mimicking D2R signaling in iMSNs with Gi-DREADDs restored the level of tonic GABAergic transmission and rescued the motor deficit. These findings indicate that DA, through D2R activation in iMSNs, regulates motor output by constraining the strength of GABAergic transmission. Lemos et al. find that targeted deletion of dopamine D2 receptors from indirect-pathway medium spiny neurons (iMSNs) leads to enhanced GABAergic transmission downstream of iMSNs. This enhanced GABAergic tone causes a Parkinsonian-like motor deficit similar to dopamine depletion models.Fil: Lemos, Julia C.. National Institutes of Health; Estados UnidosFil: Friend, Danielle M.. National Institutes of Health; Estados UnidosFil: Kaplan, Alanna R.. National Institutes of Health; Estados UnidosFil: Shin, Jung Hoon. National Institutes of Health; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Kravitz, Alexxai V.. National Institutes of Health; Estados UnidosFil: Alvarez, Veronica A.. National Institutes of Health; Estados UnidosCell Press2016-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/39463Lemos, Julia C.; Friend, Danielle M.; Kaplan, Alanna R.; Shin, Jung Hoon; Rubinstein, Marcelo; et al.; Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling; Cell Press; Neuron; 90; 4; 5-2016; 824-8380896-6273CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.neuron.2016.04.040info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0896627316301271info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4882167/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:36:36Zoai:ri.conicet.gov.ar:11336/39463instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:36:36.395CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling
title Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling
spellingShingle Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling
Lemos, Julia C.
Dopamina
Parkinson
Receptor D2
title_short Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling
title_full Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling
title_fullStr Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling
title_full_unstemmed Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling
title_sort Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling
dc.creator.none.fl_str_mv Lemos, Julia C.
Friend, Danielle M.
Kaplan, Alanna R.
Shin, Jung Hoon
Rubinstein, Marcelo
Kravitz, Alexxai V.
Alvarez, Veronica A.
author Lemos, Julia C.
author_facet Lemos, Julia C.
Friend, Danielle M.
Kaplan, Alanna R.
Shin, Jung Hoon
Rubinstein, Marcelo
Kravitz, Alexxai V.
Alvarez, Veronica A.
author_role author
author2 Friend, Danielle M.
Kaplan, Alanna R.
Shin, Jung Hoon
Rubinstein, Marcelo
Kravitz, Alexxai V.
Alvarez, Veronica A.
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Dopamina
Parkinson
Receptor D2
topic Dopamina
Parkinson
Receptor D2
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Bradykinesia is a prominent phenotype of Parkinson's disease, depression, and other neurological conditions. Disruption of dopamine (DA) transmission plays an important role, but progress in understanding the exact mechanisms driving slowness of movement has been impeded due to the heterogeneity of DA receptor distribution on multiple cell types within the striatum. Here we show that selective deletion of DA D2 receptors (D2Rs) from indirect-pathway medium spiny neurons (iMSNs) is sufficient to impair locomotor activity, phenocopying DA depletion models of Parkinson's disease, despite this mouse model having intact DA transmission. There was a robust enhancement of GABAergic transmission and a reduction of in vivo firing in striatal and pallidal neurons. Mimicking D2R signaling in iMSNs with Gi-DREADDs restored the level of tonic GABAergic transmission and rescued the motor deficit. These findings indicate that DA, through D2R activation in iMSNs, regulates motor output by constraining the strength of GABAergic transmission. Lemos et al. find that targeted deletion of dopamine D2 receptors from indirect-pathway medium spiny neurons (iMSNs) leads to enhanced GABAergic transmission downstream of iMSNs. This enhanced GABAergic tone causes a Parkinsonian-like motor deficit similar to dopamine depletion models.
Fil: Lemos, Julia C.. National Institutes of Health; Estados Unidos
Fil: Friend, Danielle M.. National Institutes of Health; Estados Unidos
Fil: Kaplan, Alanna R.. National Institutes of Health; Estados Unidos
Fil: Shin, Jung Hoon. National Institutes of Health; Estados Unidos
Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Kravitz, Alexxai V.. National Institutes of Health; Estados Unidos
Fil: Alvarez, Veronica A.. National Institutes of Health; Estados Unidos
description Bradykinesia is a prominent phenotype of Parkinson's disease, depression, and other neurological conditions. Disruption of dopamine (DA) transmission plays an important role, but progress in understanding the exact mechanisms driving slowness of movement has been impeded due to the heterogeneity of DA receptor distribution on multiple cell types within the striatum. Here we show that selective deletion of DA D2 receptors (D2Rs) from indirect-pathway medium spiny neurons (iMSNs) is sufficient to impair locomotor activity, phenocopying DA depletion models of Parkinson's disease, despite this mouse model having intact DA transmission. There was a robust enhancement of GABAergic transmission and a reduction of in vivo firing in striatal and pallidal neurons. Mimicking D2R signaling in iMSNs with Gi-DREADDs restored the level of tonic GABAergic transmission and rescued the motor deficit. These findings indicate that DA, through D2R activation in iMSNs, regulates motor output by constraining the strength of GABAergic transmission. Lemos et al. find that targeted deletion of dopamine D2 receptors from indirect-pathway medium spiny neurons (iMSNs) leads to enhanced GABAergic transmission downstream of iMSNs. This enhanced GABAergic tone causes a Parkinsonian-like motor deficit similar to dopamine depletion models.
publishDate 2016
dc.date.none.fl_str_mv 2016-05
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/39463
Lemos, Julia C.; Friend, Danielle M.; Kaplan, Alanna R.; Shin, Jung Hoon; Rubinstein, Marcelo; et al.; Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling; Cell Press; Neuron; 90; 4; 5-2016; 824-838
0896-6273
CONICET Digital
CONICET
url http://hdl.handle.net/11336/39463
identifier_str_mv Lemos, Julia C.; Friend, Danielle M.; Kaplan, Alanna R.; Shin, Jung Hoon; Rubinstein, Marcelo; et al.; Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling; Cell Press; Neuron; 90; 4; 5-2016; 824-838
0896-6273
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.neuron.2016.04.040
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0896627316301271
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4882167/
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Cell Press
publisher.none.fl_str_mv Cell Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1844613149158801408
score 13.070432

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