MK-801- and memantine-induced locomotor hyperactivity is attenuated by conditional loss of dopamine D2 receptors in select forebrain neurons

Disruption of cerebral cortical interneuron maturation has been implicated in the pathophysiology of schizophrenia, and NMDA receptor antagonists are widely used to model psychosis-relevant behavioral phenotypes in rodents. Dopamine D2 receptors (D2Rs) are expressed on cortical GABAergic interneurons derived from the medial ganglionic eminence (MGE), where they regulate inhibitory circuit function during development and in adulthood. Whether D2R signaling on MGE-derived interneurons gates the locomotor and stereotypic responses to NMDA receptor antagonism has not been established. Here, we used mice with conditional deletion of D2Rs from developing Nkx2.1-lineage GABAergic interneurons (D2R-cKO) to examine this question across a dose-response range of MK-801 (0.1, 0.3, and 0.6 mg/kg) and a single dose of memantine (30 mg/kg), using a three-day open-field protocol. D2R-cKO mice and littermate controls did not differ in baseline locomotion or within-session or between-session habituation, confirming intact basal motor function. Following MK-801, D2R-cKO mice exhibited significantly blunted locomotor hyperactivity at the two behaviorally active doses (0.3 and 0.6 mg/kg), with no genotype difference at the lowest dose. Vertical activity echoed the horizontal locomotor activity findings. This locomotor attenuation was fully replicated with a second NMDA receptor antagonist, memantine, in an independent cohort. In contrast, drug-induced behavioral stereotypies were relatively less impacted than horizontal locomotion or rearing. In contrast, biological sex strongly influenced stereotypic behavior, with males showing higher counts than females across active doses but did not have effects on locomotion. Novel components of the current study include a robust dose-response characterization, the documentation of a behavioral dissociation between locomotion and stereotypy, and the replication of the phenotype using a pharmacologically distinct NMDA receptor antagonist. These findings demonstrate that D2R signaling within MGE-derived GABAergic neurons modulates the locomotor component of NMDA antagonist-induced behavioral activation.