Sustained Gq-Protein Signaling Disrupts Striatal Circuits via JNK.
Journal of Neuroscience. 2016-10-12; 36(41): 10611-10624
DOI: 10.1523/jneurosci.1192-16.2016
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1. J Neurosci. 2016 Oct 12;36(41):10611-10624.
Sustained Gq-Protein Signaling Disrupts Striatal Circuits via JNK.
Bellocchio L(1), Ruiz-Calvo A(2), Chiarlone A(2), Cabanas M(3), Resel E(2),
Cazalets JR(3), Blázquez C(2), Cho YH(3), Galve-Roperh I(2), Guzmán M(1).
Author information:
(1)Department of Biochemistry and Molecular Biology I, Centro de Investigación
Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto
Ramón y Cajal de Investigación Sanitaria (IRYCIS), and Instituto Universitario de
Investigación Neuroquímica (IUIN), Complutense University, 28040 Madrid, Spain,
and .
(2)Department of Biochemistry and Molecular Biology I, Centro de Investigación
Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto
Ramón y Cajal de Investigación Sanitaria (IRYCIS), and Instituto Universitario de
Investigación Neuroquímica (IUIN), Complutense University, 28040 Madrid, Spain,
and.
(3)Institute of Cognitive and Integrative Neuroscience of Aquitaine, University
of Bordeaux, 33615 Pessac Cedex, France.
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 Gs/Gi-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 Gq-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 Gq-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 Gq-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 Gq-protein-driven signals in striatal circuits under
normal and overactivated states.SIGNIFICANCE STATEMENT: 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
Gs/Gi-protein-dependent tuning of striatal neurons is fairly well known, the
precise impact and underlying mechanism of Gq-protein-dependent signals remain
unclear. Here, we show that striatal circuits can be “turned on” by acute
Gq-protein signaling or “turned off” by sustained Gq-protein signaling.
Specifically, sustained Gq-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
Gq-protein-driven signals in striatal circuits under normal and overactivated
states.
Copyright © 2016 the authors 0270-6474/16/3610611-14$15.00/0.
DOI: 10.1523/JNEUROSCI.1192-16.2016
PMID: 27733612 [Indexed for MEDLINE]