Neural substrates of psychotic-like states and cognitive impairment in a mouse model of schizophrenia and subsequent rescue by antipsychotic drugs

Abstract

This thesis aimed to understand the neural mechanisms underlying distinct symptomatology in schizophrenia, one of the most devastating neuropsychiatric disorders, from a preclinical point of view. A second major objective has been to gain insight into how the current medication affects pathological neural dynamics within the context of psychosis and cognitive impairment. Understanding how the circuit is disrupted in pathological conditions and how it is affected by the current medication may help develop new therapeutic interventions. In the present thesis, we investigated the alterations of prefrontal-hippocampal circuits in the phencyclidine (PCP), acute and subchronic, mouse model of schizophrenia and how some of these alterations can be recovered by antipsychotic drugs. We recorded neural activity in the prefrontal cortex and hippocampus of C57BL/6J mice. In the first part of the thesis, we investigated the neural substrates of psychosis-like states induced by acute PCP and the rescuing abilities of antipsychotic drugs or serotonergic agents. In the second part, we investigated the neural substrates of cognitive impairment induced by the subchronic PCP treatment. We also assessed behavioral and neurophysiological rescue by a 14-day treatment with the atypical antipsychotic drug risperidone. Acute administration of PCP produced hyper synchronization of the prefrontal cortex, desynchronization of the hippocampus and disrupted communication of prefrontal-hippocampal pathways. The atypical antipsychotic drugs risperidone and clozapine, but not typical antipsychotic drug haloperidol, reduced PCP-induced prefrontal cortex and cortical-hippocampal hypersynchrony, likely due their greater affinity for serotonin receptors. None of the substances restored hippocampal and circuit desynchronization. Furthermore, subchronic PCP-treated mice showed brain state alterations in gamma oscillations and theta-gamma cross-frequency coupling. Notably, auditory perception, working memory and long-term memory were profoundly impaired in subchronic PCP-treated mice and were accompanied by disrupted prefrontal-hippocampal functional connectivity within theta (4-12 Hz) and gamma (30-100 Hz) ranges. Finally, the chronic risperidone treatment was able to recover memory deficits and auditory perception by correcting key neurophysiological biomarkers, but was unable to restore the basal circuit dynamics.