Insights into neurobiological mechanism of probabilistic decision-making impairments in schizophrenia from Akt1 and PV interneurons in mice

Schizophrenia, a debilitating disorder with genetic and neurobiological underpinnings, often manifests cognitive deficits, including impaired decision-making. Utilizing Akt1 heterozygous mutant (HET) mice as a model, which mimic schizophrenia due to AKT1’s implication as a susceptibility gene, we investigated the involvement of Akt1 and its neural mechanisms influencing strategic decision-making to identify potential therapeutic targets for schizophrenia-associated cognitive impairments. In six experiments, we first revealed that lesions targeting the dorsomedial striatum (DMS) significantly impacted performance in a mouse version of the two-choice probabilistic decision-making task, surpassing effects observed in other striatal subregions. Behavioral assessments in HET mice unveiled notable disturbances, including reduced accumulated trials to reach criteria, diminished ratio of lose-stay behavior, elevated learning rates, and decreased choice consistency in reinforcement learning models. Moreover, we found a strong correlation between DMS local field potential power and choice behavior, particularly evident in no-reward conditions. The behavioral abnormalities observed in HET mice were restored when the DMS was chemogenetically inhibited, while their locomotor activity remained unaffected. Furthermore, RNAseq analysis and immunohistochemistry uncovered reduced expression of striatal parvalbumin (PV) interneurons in HET mice. Targeted lesioning of PV interneurons in the DMS of wild-type mice resulted in behavioral alterations mirroring those in HET mice. In summary, our findings suggest that Akt1 deficiency-induced downregulation of PV expression alters neural oscillations in the DMS, influencing choice strategies, especially in no-reward conditions during probabilistic decision-making. These results underscore the crucial involvement of AKT1 and PV interneurons in modulating strategic decision-making, with particular relevance to the understanding of schizophrenia.