Control of impulsivity by G_i-protein signalling in layer-5 pyramidal neurons of the anterior cingulate cortex.

ABSTRACT: Pathological impulsivity is a debilitating symptom of multiple psychiatric diseases with few effective treatment options. To identify druggable receptors with anti-impulsive action we developed a systematic target discovery approach combining behavioural chemogenetics and gene expression analysis. Spatially restricted inhibition of three subdivisions of the prefrontal cortex of mice revealed that the anterior cingulate cortex (ACC) regulates premature responding, a form of motor impulsivity. Probing three G-protein cascades with designer receptors, we found that the activation of G_i-signalling in layer-5 pyramidal cells (L5-PCs) of the ACC strongly, reproducibly, and selectively decreased challenge-induced impulsivity. Differential gene expression analysis across murine ACC cell-types and 402 GPCRs revealed that - among G_i-coupled receptor-encoding genes - Grm2 is the most selectively expressed in L5-PCs while alternative targets were scarce. Validating our approach, we confirmed that mGluR2 activation reduced premature responding. These results suggest G_i-coupled receptors in ACC L5-PCs as therapeutic targets for impulse control disorders.

SUBMITTER: van der Veen B 

PROVIDER: S-EPMC8172539 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature