NMDA receptor ablation in medial prefrontal cortex disrupts value updating and reward history integration.

Schizophrenia, a serious mental illness, is associated with evidence of NMDA receptor (NMDAR) dysfunction and characterized by cognitive impairments that reflect impaired value updating and feedback-driven control. However, the cellular and circuit-level mechanisms underlying these disruptions remain unclear. Here, we test how NMDA receptor (NMDAR) signaling in the medial prefrontal cortex (mPFC) contributes to adaptive decision-making by combining targeted genetic ablation in mice and systemic pharmacology. Using a CRISPR-Cas9 approach to eliminate the obligate GluN1 subunit, we induced NMDAR hypofunction centered on the mPFC and compared its effects to systemic pharmacological blockade with the NMDAR antagonist MK-801 during performance of a touchscreen-based restless bandit task. Prefrontal NMDAR ablation impaired value discrimination and weakened the use of negative feedback, indicating disrupted feedback-guided decision making. Reinforcement-learning models incorporating a choice-kernel term best captured behavior and revealed that NMDAR ablation selectively altered experience-dependent choice updating. Systemic MK-801 produced widespread impairments in control animals, reducing performance and disrupting reward-history integration, while producing more limited additional effects in animals with prefrontal NMDAR ablation. Simulations using fitted model parameters reproduced these patterns, showing convergence toward a shared impaired behavioral regime under MK-801 despite residual differences in underlying decision processes. Together, these findings indicate that prefrontal NMDAR signaling supports key components of value-based decision making, while systemic NMDAR hypofunction engages broader mechanisms that further disrupt the integration of recent experience. This work provides a mechanistic account of how localized and distributed glutamatergic dysfunction contribute to distinct components of reinforcement-learning deficits relevant to schizophrenia.