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.
Pubmed ID: 29229708 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This unknown targets D1 Dopamine Receptor
View all literature mentionsThis monoclonal targets Phospho-DARPP-32 (Ser97) (D11A5) Rabbit mAb
View all literature mentionsThis unknown targets Anti-mCherry Antibody
View all literature mentionsThis unknown targets
View all literature mentionsThis unknown targets IgG
View all literature mentionsThis monoclonal targets beta-Actin
View all literature mentionsThis polyclonal targets PPP1R1B
View all literature mentionsThis polyclonal targets PPP1R1B
View all literature mentionsThis monoclonal targets DARPP-32
View all literature mentionsThis unknown targets EAAT2
View all literature mentionsThis monoclonal targets EAAT1 (D44E2) XP Rabbit mAb
View all literature mentionsThis polyclonal targets GRM5
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsMus musculus with name B6.Cg-Tg(Drd1a-tdTomato)6Calak/J from IMSR.
View all literature mentionsMus musculus with name B6.Cg-Gt(ROSA)26Sortm9(CAG-tdTomato)Hze/J from IMSR.
View all literature mentionsMus musculus with name B6.FVB(Cg)-Tg(Adora2a-cre)KG139Gsat/Mmucd from MMRRC.
View all literature mentionsMus musculus with name STOCK Tg(Drd1-cre)EY217Gsat/Mmucd from MMRRC.
View all literature mentionsThis unknown targets D1 Dopamine Receptor
View all literature mentions