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Neuronal glutamate transporters control dopaminergic signaling and compulsive behaviors

Stefania Bellini, Kelsey E. Fleming, Modhurika De, John P. McCauley, Maurice A. Petroccione, Lianna Y. D’Brant, Artem kachenko, SoYoung Kwon, Lindsey A. Jones, View ORCID ProfileAnnalisa Scimemi
doi: https://doi.org/10.1101/224477
Stefania Bellini
SUNY Albany, Department of Biology, 1400 Washington Avenue, Albany (NY) 12222, USA
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Kelsey E. Fleming
SUNY Albany, Department of Biology, 1400 Washington Avenue, Albany (NY) 12222, USA
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Modhurika De
SUNY Albany, Department of Biology, 1400 Washington Avenue, Albany (NY) 12222, USA
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John P. McCauley
SUNY Albany, Department of Biology, 1400 Washington Avenue, Albany (NY) 12222, USA
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Maurice A. Petroccione
SUNY Albany, Department of Biology, 1400 Washington Avenue, Albany (NY) 12222, USA
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Lianna Y. D’Brant
SUNY Albany, Department of Biology, 1400 Washington Avenue, Albany (NY) 12222, USA
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Artem kachenko
SUNY Albany, Department of Biology, 1400 Washington Avenue, Albany (NY) 12222, USA
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SoYoung Kwon
SUNY Albany, Department of Biology, 1400 Washington Avenue, Albany (NY) 12222, USA
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Lindsey A. Jones
SUNY Albany, Department of Biology, 1400 Washington Avenue, Albany (NY) 12222, USA
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Annalisa Scimemi
SUNY Albany, Department of Biology, 1400 Washington Avenue, Albany (NY) 12222, USA
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  • ORCID record for Annalisa Scimemi
  • For correspondence: scimemia@gmail.com
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ABSTRACT

There is an ongoing debate on the contribution of the neuronal glutamate transporter EAAC1 to the onset of compulsive behaviors. Here we use 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-expressing striatal neurons of mice expressing EAAC1 leads to reduced D1R expression 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 (mGluRI) in the striatum and, by doing so, it promotes D1R expression. Targeted activation of signaling cascades coupled to mGluRI in mice expressing EAAC1 reduces D1R expression and triggers repeated motor behaviors in mice. These findings provide new information on the molecular basis of OCD and suggest new avenues for its treatment.

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  • CONFLICT OF INTEREST The authors declare no competing financial interests.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted December 03, 2017.
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Neuronal glutamate transporters control dopaminergic signaling and compulsive behaviors
Stefania Bellini, Kelsey E. Fleming, Modhurika De, John P. McCauley, Maurice A. Petroccione, Lianna Y. D’Brant, Artem kachenko, SoYoung Kwon, Lindsey A. Jones, Annalisa Scimemi
bioRxiv 224477; doi: https://doi.org/10.1101/224477
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Neuronal glutamate transporters control dopaminergic signaling and compulsive behaviors
Stefania Bellini, Kelsey E. Fleming, Modhurika De, John P. McCauley, Maurice A. Petroccione, Lianna Y. D’Brant, Artem kachenko, SoYoung Kwon, Lindsey A. Jones, Annalisa Scimemi
bioRxiv 224477; doi: https://doi.org/10.1101/224477

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