Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling
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 heterogeneit...
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08966273_v90_n4_p824_Lemos http://hdl.handle.net/20.500.12110/paper_08966273_v90_n4_p824_Lemos |
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paper:paper_08966273_v90_n4_p824_Lemos2023-06-08T15:49:13Z Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling Rubinstein, Marcelo 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 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 . Fil:Rubinstein, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2016 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08966273_v90_n4_p824_Lemos http://hdl.handle.net/20.500.12110/paper_08966273_v90_n4_p824_Lemos |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
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Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 Rubinstein, Marcelo Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling |
| topic_facet |
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 |
| 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. © 2016 . |
| author |
Rubinstein, Marcelo |
| author_facet |
Rubinstein, Marcelo |
| author_sort |
Rubinstein, Marcelo |
| title |
Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling |
| 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 |
| publishDate |
2016 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08966273_v90_n4_p824_Lemos http://hdl.handle.net/20.500.12110/paper_08966273_v90_n4_p824_Lemos |
| work_keys_str_mv |
AT rubinsteinmarcelo enhancedgabatransmissiondrivesbradykinesiafollowinglossofdopamined2receptorsignaling |
| _version_ |
1768545470301339648 |