Neural Substrates of Psychosis and Cognitive Impairment in Mouse Models of Schizophrenia

Abstract

Schizophrenia is a multifaceted psychiatric disorder characterized by positive, negative, and cognitive symptoms. While its cellular mechanisms remain elusive, the prefrontal cortex (PFC) and hippocampus (HPC) are central to the disorder’s pathophysiology, with patients showing structural and functional anomalies in these regions. We examined aberrant neural activity within prefrontal-hippocampal circuits in mice treated with phencyclidine (PCP), a psychostimulant that produces schizophrenia symptoms in humans and rodents. Acute PCP administration induced psychosis that correlated with prefrontal hypersynchronization, hippocampal desynchronization, and disrupted circuit connectivity. The atypical antipsychotic risperidone alleviated cortical disturbances with minimal impact on the HPC, whereas the classical neuroleptic haloperidol exacerbated circuit disruptions, revealing distinct effects of atypical and classical APDs on prefrontal-hippocampal dynamics. Notably, serotonin 5-HT2AR antagonism and 5-HT1AR agonism outperformed risperidone in restoring prefrontal-hippocampal dynamics. Subchronic PCP treatment produced enduring cognitive impairments, including deficits in short- and long-term memory, auditory processing and attention, which were accompanied by increased prefrontal and reduced hippocampal neural synchronization. Chronic risperidone improved impaired memory and auditory processing, but not auditory attention, while mitigating hippocampal disturbances, providing a neural framework for its cognitive benefits in schizophrenia. These findings suggest that cortical hypersynchronization contributes to positive symptoms, whereas hippocampal desynchronization and disrupted connectivity underlie cognitive deficits in schizophrenia.