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Abstract:

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. © 2016 .

Registro:

Documento: Artículo
Título:Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling
Autor:Lemos, J.C.; Friend, D.M.; Kaplan, A.R.; Shin, J.H.; Rubinstein, M.; Kravitz, A.V.; Alvarez, V.A.
Filiación:National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, United States
National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, United States
National Institute on Drug Abuse, NIH, Bethesda, MD 20892, United States
Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, CONICET, Buenos Aires, C1428ADN, Argentina
FCEN, Universidad de Buenos Aires, Buenos Aires, C1428EGA, Argentina
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, United States
Palabras clave:dopamine 2 receptor; 4 aminobutyric acid; dopamine; dopamine 2 receptor; animal experiment; animal tissue; Article; bradykinesia; brain nerve cell; controlled study; corpus striatum; depletion; dopaminergic transmission; GABAergic transmission; gene deletion; globus pallidus; in vivo study; indirect pathway medium spiny neuron; locomotion; mouse; mouse model; nerve cell; nerve cell membrane potential; nonhuman; Parkinson disease; priority journal; signal transduction; animal; hypokinesia; metabolism; physiology; signal transduction; substantia nigra; transgenic mouse; Animals; Corpus Striatum; Dopamine; gamma-Aminobutyric Acid; Globus Pallidus; Hypokinesia; Mice, Transgenic; Neurons; Parkinson Disease; Receptors, Dopamine D2; Signal Transduction; Substantia Nigra
Año:2016
Volumen:90
Número:4
Página de inicio:824
Página de fin:838
DOI: http://dx.doi.org/10.1016/j.neuron.2016.04.040
Título revista:Neuron
Título revista abreviado:Neuron
ISSN:08966273
CODEN:NERNE
CAS:4 aminobutyric acid, 28805-76-7, 56-12-2; dopamine, 51-61-6, 62-31-7; Dopamine; gamma-Aminobutyric Acid; Receptors, Dopamine D2
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08966273_v90_n4_p824_Lemos

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Citas:

---------- APA ----------
Lemos, J.C., Friend, D.M., Kaplan, A.R., Shin, J.H., Rubinstein, M., Kravitz, A.V. & Alvarez, V.A. (2016) . Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling. Neuron, 90(4), 824-838.
http://dx.doi.org/10.1016/j.neuron.2016.04.040
---------- CHICAGO ----------
Lemos, J.C., Friend, D.M., Kaplan, A.R., Shin, J.H., Rubinstein, M., Kravitz, A.V., et al. "Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling" . Neuron 90, no. 4 (2016) : 824-838.
http://dx.doi.org/10.1016/j.neuron.2016.04.040
---------- MLA ----------
Lemos, J.C., Friend, D.M., Kaplan, A.R., Shin, J.H., Rubinstein, M., Kravitz, A.V., et al. "Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling" . Neuron, vol. 90, no. 4, 2016, pp. 824-838.
http://dx.doi.org/10.1016/j.neuron.2016.04.040
---------- VANCOUVER ----------
Lemos, J.C., Friend, D.M., Kaplan, A.R., Shin, J.H., Rubinstein, M., Kravitz, A.V., et al. Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling. Neuron. 2016;90(4):824-838.
http://dx.doi.org/10.1016/j.neuron.2016.04.040