Abstract
Human postmortem studies suggest a major role for abnormalities in GABAergic interneurons in the prefrontal cortex in schizophrenia. Cortical interneurons differentiated from induced pluripotent stem cells (iPSCs) of schizophrenia subjects showed significantly lower levels of glutamate decarboxylase 67 (GAD67), replicating findings from multiple postmortem studies, as well as reduced levels of synaptic proteins gehpyrin and NLGN2. Co-cultures of the interneurons with excitatory cortical pyramidal neurons from schizophrenia iPSCs showed reduced synaptic puncta density and lower action potential frequency. NLGN2 overexpression in schizophrenia neurons rescued synaptic puncta deficits while NLGN2 knockdown in healthy neurons resulted in reduced synaptic puncta density. Schizophrenia interneurons also had significantly smaller nuclear area, suggesting an innate oxidative stressed state. The antioxidant N-acetylcysteine increased the nuclear area in schizophrenia interneurons, increased NLGN2 expression and rescued synaptic deficits. These results implicate specific deficiencies in the synaptic machinery in cortical interneurons as critical regulators of synaptic connections in schizophrenia and point to a nexus between oxidative stress and NLGN2 expression in mediating synaptic deficits in schizophrenia.
Highlights
Schizophrenia (SCZ) is a chronic and debilitating psychiatric disorder characterized by hallucinations, paranoid delusions, disordered thought processes, and cognitive deficits[1]
A similar pattern has been reported in SCZ brains—density of parvalbumin expressing neurons was not different in SCZ but PARVB mRNA levels were significantly lower in the prefrontal cortex[15,20]
We found that GAD1 levels were significantly lower in SCZ interneurons (Fig. 1k), which recapitulates well-replicated postmortem findings of reduced levels of GAD1 expression in the prefrontal cortex in SCZ21,22
Summary
Schizophrenia (SCZ) is a chronic and debilitating psychiatric disorder characterized by hallucinations, paranoid delusions, disordered thought processes, and cognitive deficits[1]. The onset of psychosis is typically in adolescence or early adulthood and it follows a chronic course requiring treatment for the rest of a person’s life[2,3]. Patients have an elevated risk of suicide compared to the general population, and suicide is the cause of over 10% of deaths in patients with psychotic disorders[4]. SCZ is a significant contributor to the global burden of disease— SCZ is the 8th leading cause of disability-adjusted life year worldwide and psychosis is ranked as the 3rd most disabling condition[5,6]. There is an urgent need for understanding the cellular-molecular underpinnings of SCZ that can be leveraged for the development of novel therapeutics that can bring about meaningful improvement in the functional outcomes for patients with SCZ8,9
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