Long-Lasting Rescue of Network and Cognitive Dysfunction in a Genetic Schizophrenia Model

Although sensitizing processes occur earlier, schizophrenia is diagnosed in young adulthood, which suggests that it might involve a pathological transition during late brain development in predisposed individuals. Parvalbumin (PV) interneuron alterations have been noticed, but their role in the disease is unclear. Here we demonstrate that adult LgDel+/− mice, a genetic model of schizophrenia, exhibit PV neuron hypo-recruitment and associated chronic PV neuron plasticity together with network and cognitive deficits. All these deficits can be permanently rescued by chemogenetic activation of PV neurons or D2R antagonist treatments, specifically in the ventral hippocampus (vH) or medial-prefrontal cortex during a late-adolescence-sensitive time window. PV neuron alterations were initially restricted to the hippocampal CA1/subiculum, where they became responsive to treatment in late adolescence. Therefore, progression to disease in schizophrenia-model mice can be prevented by treatments supporting vH-mPFC PV network function during a sensitive time window late in adolescence, suggesting therapeutic strategies to prevent the outbreak of schizophrenia. [Display omitted] •Adult network and cognitive deficits in LgDel+/− mice mimic schizophrenia patients•Network deficits include PV neuron hypo-recruitment and chronic low-PV plasticity•Late-adolescence treatments long-lastingly prevent deficit appearance in the adult•LgDel+/− rescue involves support of vH-mPFC PV network during sensitive time window Repeated pharmacological treatment or manipulation of neuronal circuit activity during a well-defined time window in late adolescence produces complete and long-lasting rescue of network and cognitive deficits in a genetic mouse model of schizophrenia.