Prefrontal D2- dopamine receptor deactivates top-down inhibitory control by regulating striatal cholinergic interneurons

Inhibitory control is a core cognitive function preventing the expression of maladaptive behaviors. This function is overridden in mental illnesses including bipolar disorder, autism spectrum disorders and schizophrenia, causing maladaptive psychomotor agitation. We developed intersectional CRISPR/Cas9 targeting approaches in adult mice to identify receptor/circuit selective mechanisms responsible for inactivation of inhibitory control in two models of amphetamine-induced psychomotor agitation. Inactivation of dopamine D2-receptors in the medial-prefrontal cortex (mPFC) abolished amphetamine-induced: psychomotor agitation, motor sensitization, and cAMP-associated transcriptome changes in the striatum. Further characterization using intersectional projection preparations indicate that these deficits implicate D2-receptors expressed on projection neurons innervating cholinergic interneurons of the dorsomedial striatum (DMS). Trans-synaptic targeting of acetylcholine production in DMS neurons receiving these projections restored psychomotor agitation in mice lacking mPFC D2- receptor expression. These findings identify a circuit by which activation of cortical D2-receptor circumvent an acetylcholine-mediated inhibition of DMS functions by the mPFC to promote psychomotor activation. To investigate the impact of mPFC D2R deficit on striatal responses to amphetamine, we performed RNA-seq analysis using mice that D2R was targeting using CRISPR/Cas9 strategy and received an acute administration of amphetamine (3mg/kg, i.p). D2RCre_floxCas9-EGFP mice received virus injection in mPFC of AAV5 D2R-sgRNA (PFC_D2R-KO mice) or AAV5 syn-mCherry (control mice). Treatment: 5 days of saline injection (ip) followed by a single injection of amphetamine (3mg/kg, ip) on the challenge day (day9). 4 groups: VV-Control = vehicle treatment in control mice; VA-Control = amphetamine treatment in control mice; VV-KO = vehicle treatment in PFC_D2R-KO mice; VA-KO = amphetamine treatment in PFC_D2R-KO mice.