Beschreibung:
<jats:p>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<jats:sub>s</jats:sub>/G<jats:sub>i</jats:sub>-protein-dependent tuning of striatal neurons is fairly well known, the precise impact and underlying mechanism of G<jats:sub>q</jats:sub>-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<jats:sub>q</jats:sub>-protein signaling impairs the functionality of striatal neurons and we unveil the precise molecular mechanism underlying this process: a phospholipase C/Ca<jats:sup>2+</jats:sup>/proline-rich tyrosine kinase 2/cJun<jats:italic>N</jats:italic>-terminal kinase pathway. Moreover, engagement of this intracellular signaling route was functionally active in the mouse dorsal striatum<jats:italic>in vivo</jats:italic>, as proven by the disruption of neuronal integrity and behavioral tasks. To analyze this effect anatomically, we manipulated G<jats:sub>q</jats:sub>-protein-dependent signaling selectively in neurons belonging to the direct or indirect striatal pathway. Acute G<jats:sub>q</jats:sub>-protein activation in direct-pathway or indirect-pathway neurons produced an enhancement or a decrease, respectively, of activity-dependent parameters. In contrast, sustained G<jats:sub>q</jats:sub>-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<jats:sub>q</jats:sub>-protein-driven signals in striatal circuits under normal and overactivated states.</jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT</jats:bold>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. Whereas the G<jats:sub>s</jats:sub>/G<jats:sub>i</jats:sub>-protein-dependent tuning of striatal neurons is fairly well known, the precise impact and underlying mechanism of G<jats:sub>q</jats:sub>-protein-dependent signals remain unclear. Here, we show that striatal circuits can be “turned on” by acute G<jats:sub>q</jats:sub>-protein signaling or “turned off” by sustained G<jats:sub>q</jats:sub>-protein signaling. Specifically, sustained G<jats:sub>q</jats:sub>-protein signaling inactivates striatal neurons by an intracellular pathway that relies on cJun<jats:italic>N</jats:italic>-terminal kinase. Overall, this study sheds new light onto the molecular mechanism and functional relevance of G<jats:sub>q</jats:sub>-protein-driven signals in striatal circuits under normal and overactivated states.</jats:p>