IMPAIRED EFFORT ALLOCATION FOR REWARD AND IMPULSIVITY IN THE GRIN2A HYPOFUNCTION MOUSE MODEL FOR SCHIZOPHRENIA

Motivational deficits and impaired ability to anticipate, update, and maintain representations of reward value are central psychopathological features driving negative and cognitive symptoms in schizophrenia (SHZ). The underlying pathophysiological mechanisms remain poorly understood, creating a significant barrier to developing targeted treatments. SHZ carries strong genetic risk and rare loss of function variants in the GRIN2A subunit of NMDA receptors confers substantial disease risk.
GRIN2A heterozygous knockout mice (GRIN2A-HET), modeling GRIN2A hypofunction, offers a promising preclinical model to dissect physiological dysfunctions relevant to SHZ. In this study, we examined reward processing in GRIN2A-HET mice using a progressive ratio (PR) schedule to quantify motivation and effort allocation, and five-choice serial reaction time task (5-CSRTT) with a variable inter-trial interval (vITI) to probe adaptation to uncertain rewards.
In the PR task, GRIN2A-HET mice showed a marked and consistent reduction in effort expenditure for reward, particularly under ad libitum feeding when motivation is driven by palatability rather than homeostatic need. GRIN2A-HET mice performed comparably to controls on low effort trials, indicating preserved task engagement and hedonic consumption. In the 5-CSRTT, GRIN2A-HET mice required extended training, exhibited higher impulsivity struggling to adapt to a vITI, reflecting deficits to cope with uncertain rewards.
The coexistence of avolition and impulsivity mirrors the heterogeneity of symptoms of SHZ suggesting GRIN2A-HET mice did not display a generalized motivational impairment. Instead, they exhibited deficits in computing reward value and adapting behavior to cost–benefit trade offs and reward uncertainty, aligning with neurocognitive abnormalities in reward processing as observed in SHZ.