Sustained Gq-Protein Signaling Disrupts Striatal Circuits via JNK

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_i-protein-dependent tuning of striatal neurons is fairly well known, the precise impact and underlying mechanism of G_q-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 G_q-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.

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_s/G_i-protein-dependent tuning of striatal neurons is fairly well known, the precise impact and underlying mechanism of G_q-protein-dependent signals remain unclear. Here, we show that striatal circuits can be "turned on" by acute G_q-protein signaling or "turned off" by sustained G_q-protein signaling. Specifically, sustained G_q-protein signaling inactivates striatal neurons by an intracellular pathway that relies on cJun N-terminal kinase. Overall, this study sheds new light onto the molecular mechanism and functional relevance of G_q-protein-driven signals in striatal circuits under normal and overactivated states.