Neuronal glutamate transporters control dopaminergic signaling and compulsive behaviors

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 STATEMENTGenetic 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.

Early-life stress induces EAAC1 expression reduction and attention-deficit and depressive behaviors in adolescent rats

“…Interestingly, EAAC1 (−/−) mice showed impulsive-like exploration, similar to NMS rats (EAAC1 WT, 50.33 10.16 ± 1.92; EAAC1 (−/−), 17.53 ± 3.00; t(33) = 2.163, P < 0.05) (Fig. 7m), corroborating the results of a previous report 33 . These results indicate that EAAC1 (−/−) mice display deficits in orienting and nonselective attention behavior.…”

“…The sequential patterned strokes performed during grooming are reminiscent of the excessive and repetitive hand-washing behaviors of patients with OCD 60 . Regarding the different grooming behavior phenotypes, Slc1al/EAAC1-null mice demonstrated no significant changes in 8-to 16-wk-old mice 45 , and others have reported increased grooming activity in EAAC1 knock-out mice (P14-P35) 33 . Additionally, other reports have published evidence for a role of EAAC1 in schizophrenia.…”

Behavioral and synaptic alterations relevant to obsessive-compulsive disorder in mice with increased EAAT3 expression

“…Our results are in agreement with this hypothesis, by showing that EAAT3 glo /CMKII mice display increased behaviors that are relevant to OCD. Of note, several reports using different mouse models fully or partially lacking EAAT3 have shown unaltered baseline anxiety-like or repetitive behaviors, indirectly supporting the potential involvement of EAAT3 gain-of-function in behaviors relevant to OCD [39,40,60] (however, see [61]).…”

Single Synapse Indicators of Impaired Glutamate Clearance Derived from Fast iGluuImaging of Cortical Afferents in the Striatum of Normal and Huntington (Q175) Mice

“…A question receiving growing attention in the field of synaptic plasticity and dysfunction is the role of other glutamate uptake mechanisms. Bellini et al (2018) illuminated the role of Glu uptake from two sides: pathology and functional rescue. Their convincing evidence suggests that the neuronal Glu transporter EAAT3 (EAAC1) ensures long-term synaptic activity by reducing the activation of mGluR1 in the striatum.…”