Altered striatal dopamine dynamics and behavior in Grin2a mutant mice, a genetic mouse model of schizophrenia

Abstract

Schizophrenia (SCZ), a complex psychiatric disorder with a strong genetic basis, is thought to involve, at least in part, dopamine dysregulation in the striatum. Recent large-scale exome sequencing has identified multiple SCZ risk genes, including GRIN2A (encoding an NMDA (N-methyl-D-aspartate) receptor subunit) and AKAP11 (encoding a protein kinase A binding protein), which is also a risk gene for bipolar disorder (BD). However, the mechanisms by which these genetic risk factors perturb dopamine circuits and cause psychotic symptoms remain poorly understood. We asked how behavior, dorsomedial striatal dopamine (DA) dynamics and the activity of D1-/D2-spiny projection neurons (SPNs) were altered in Grin2a and Akap11 mutants. In the open field, Grin2a knockout mice display hyperlocomotion and an abnormal organization of naturalistic behaviors. They also displayed heightened behavioral responses to objects and auditory stimuli. Grin2a heterozygous animals mostly showed intermediate phenotypes, suggesting a dose-dependent effect of Grin2a loss. Further, Grin2a knockout mutants exhibited aberrant dopamine events, altered coupling of dopamine with locomotor features, and exaggerated stimuli-evoked dopamine responses. Notably, heterozygous animals also showed altered striatal SPN events in the open field reflecting dysregulated neural activity in both dSPNs and iSPNs. Compared to Grin2a mutants, Akap11 mutants displayed opposite phenotypes, showing reduced locomotion with a shift from high- to low-velocity movement and distinct alterations in striatal neural activity. Together, GRIN2A (SCZ risk) and AKAP11 (BD/SCZ risk) mutations induce different, often opposite, effects on striatal dopamine signaling and behavior, suggesting that these two risk genes act through distinct mechanisms.