Grin2a knockout in adolescent dopamine neurons disrupts prediction error signaling and produces a phenotype relevant to schizophrenia.

Adolescence is associated with the emergence of several psychiatric disorders including schizophrenia. Recent studies have identified both common and rare variants of the GRIN2A gene as risk factors for schizophrenia. GRIN2A encodes the GluN2A subunit of the NMDA receptor and is developmentally regulated with low cortical expression at birth that reaches adult levels in adolescence. While global knockouts of Grin2a produce abnormal behavior in mice, little is known about the functional consequences of manipulating this gene specifically in dopamine neurons, a cell type implicated in schizophrenia pathophysiology. We find that, unlike cortical regions where GluN2A levels remain stable throughout adolescence, GluN2A naturally declines in dopamine neuron-containing brain regions in this developmental period. This suggests that adolescent dopamine neurons may be especially vulnerable to further reductions of GluN2A caused by damaging GRIN2A variants. Consistent with this idea, we find that a genetically driven reduction of Grin2a in midbrain dopamine neurons of adolescent rats is sufficient to recapitulate behaviors that are consistent with some aspects of positive symptoms of schizophrenia. These include hypersensitivity to amphetamine, diminished effort optimization, impaired ability to use feedback to modify motivated actions, and disrupted dopamine release during prediction error signaling. Computational modeling of the behavioral data further revealed reduced capacity to gate associative processes based on previous learning. These data describe a novel role for GluN2A-containing dopamine neurons in prediction error signaling and provide a rodent model to explore how mutations in GRIN2A may contribute to the latent presentation of dopamine-related symptoms in schizophrenia.