Neuronal Glutamate Transporters Control Dopaminergic Signaling and Compulsive Behaviors.

Autor:	Bellini S; State University of New York, Albany, New York 12222, and., Fleming KE; State University of New York, Albany, New York 12222, and., De M; State University of New York, Albany, New York 12222, and., McCauley JP; State University of New York, Albany, New York 12222, and., Petroccione MA; State University of New York, Albany, New York 12222, and., D'Brant LY; State University of New York, Albany, New York 12222, and., Tkachenko A; State University of New York, Albany, New York 12222, and., Kwon S; State University of New York, Albany, New York 12222, and.; Emma Willard School, 285 Pawling Ave, Troy, NY 12180., Jones LA; State University of New York, Albany, New York 12222, and., Scimemi A; State University of New York, Albany, New York 12222, and scimemia@gmail.com.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2018 Jan 24; Vol. 38 (4), pp. 937-961. Date of Electronic Publication: 2017 Dec 11.
DOI:	10.1523/JNEUROSCI.1906-17.2017
Abstrakt:	There is an ongoing debate on the contribution of the neuronal glutamate transporter EAAC1 to the onset of compulsive behaviors. Here, we used behavioral, electrophysiological, molecular, and viral approaches in male and female mice to identify the molecular and cellular mechanisms by which EAAC1 controls the execution of repeated motor behaviors. Our findings show that, in the striatum, a brain region implicated with movement execution, EAAC1 limits group I metabotropic glutamate receptor (mGluRI) activation, facilitates D1 dopamine receptor (D1R) expression, and ensures long-term synaptic plasticity. Blocking mGluRI in slices from mice lacking EAAC1 restores D1R expression and synaptic plasticity. Conversely, activation of intracellular signaling pathways coupled to mGluRI in D1R-containing striatal neurons of mice expressing EAAC1 leads to reduced D1R protein level and increased stereotyped movement execution. These findings identify new molecular mechanisms by which EAAC1 can shape glutamatergic and dopaminergic signals and control repeated movement execution. SIGNIFICANCE STATEMENT Genetic studies implicate Slc1a1 , a gene encoding the neuronal glutamate transporter EAAC1, with obsessive-compulsive disorder (OCD). EAAC1 is abundantly expressed in the striatum, a brain region that is hyperactive in OCD. What remains unknown is how EAAC1 shapes synaptic function in the striatum. Our findings show that EAAC1 limits activation of metabotropic glutamate receptors (mGluRIs) in the striatum and, by doing so, promotes D1 dopamine receptor (D1R) expression. Targeted activation of signaling cascades coupled to mGluRIs in mice expressing EAAC1 reduces D1R expression and triggers repeated motor behaviors. These findings provide new information on the molecular basis of OCD and suggest new avenues for its treatment. (Copyright © 2018 the authors 0270-6474/18/380937-25$15.00/0.)
Databáze:	MEDLINE
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