期刊
JOURNAL OF NEUROSCIENCE
卷 36, 期 41, 页码 10611-10624出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1192-16.2016
关键词
cJun N-terminal kinase; G-protein-coupled receptor; medium spiny neuron; striatal circuit
资金
- Spanish Ministerio de Economia y Competitividad (MINECO/FEDER) [SAF2012-35759, SAF2015-64945-R]
- Comunidad de Madrid [S2010/BMD-2308]
- EMBO Long-Term Fellowship [ALTF 975-2011]
- Spanish Ministerio de Economia y Competitividad (FPI Program)
- French Ministry of Higher Education and Research
The dorsal striatum is a major input structure of the basal ganglia and plays a key role in the control of vital processes such as motor behavior, cognition, and motivation. The functionality of striatal neurons is tightly controlled by various metabotropic receptors. Whereas the G(s)/G(1)-protein-dependent tuning of striatal neurons is fairly well known, the precise impact and underlying mechanism of Gq-protein-dependent signals remain poorly understood. Here, using different experimental approaches, especially designer receptor exclusively activated by designer drug (DREADD) chemogenetic technology, we found that sustained activation of G(q)-protein signaling impairs the functionality of striatal neurons and we unveil the precise molecular mechanism underlying this process: a phospholipase C/Ca2+/proline-rich tyrosine kinase 2/cJun N-terminal kinase pathway. Moreover, engagement of this intracellular signaling route was functionally active in the mouse dorsal striatum in vivo, as proven by the disruption of neuronal integrity and behavioral tasks. To analyze this effect anatomically, we manipulated G(q)-protein-dependent signaling selectively in neurons belonging to the direct or indirect striatal pathway. Acute Gq-protein activation in direct-pathway or indirect-pathway neurons produced an enhancement or a decrease, respectively, of activity-dependent parameters. In contrast, sustained G(q)-protein activation impaired the functionality of direct-pathway and indirect-pathway neurons and disrupted the behavioral performance and electroencephalography-related activity tasks controlled by either anatomical framework. Collectively, these findings define the molecular mechanism and functional relevance of G(q)-protein-driven signals in striatal circuits under normal and overactivated states.
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