The long-lasting burden of major neuropsychiatric disorders, such as schizophrenia, results from disruption of cognitive performance in daily life. Impairment of long-range communication between two brain regions, the prefrontal cortex and hippocampus, has been identified as the core substrate of disease-specific mnemonic and executive deficits. While it has been hypothesized that this impairment emerges long before the first clinical symptoms, technical and ethical limitations of non-invasive investigations in high-risk infants precluded the elucidation of ontogenetic mechanisms underlying the pathophysiology of disease. Using mouse models of disease’s etiology, we recently identified the de-coupling of prefrontal-hippocampal networks during early development as potential mechanism underlying adult circuit dysfunction. However, it is still unknown, which neuronal populations are particularly affected and critically contribute to the disease-related defects of long-range communication in the brain. The proposal aims to uncover the cellular identity of circuits that are compromised early in life in mouse models of schizophrenia and elucidate the long-lasting impact of early dysfunction on the cognitive performance at adult age. The results of the project identify a specific neuronal population in the prefrontal cortex as vulnerable to the dual action of genetic deficits and environmental stressors early in life. Through a tight connectivity with the hippocampus and other cortical areas, these prefrontal neurons critically contribute to the early wiring of circuits involved in cognitive processing. On a flip side, their dysfunction during the time window when the circuits are shaped, has major long-lasting consequences on the cognitive performance. The vulnerability of these prefrontal neurons (“psychocells”) accompanied by a identification of underlying molecular and synaptic mechanisms bears also a chance to develop future therapies.
