Synaptic deficits in iPSC-derived cortical interneurons in schizophrenia are mediated by NLGN2 and rescued by N-acetylcysteine
| Autor: | Rakesh Karmacharya, Donna L. McPhie, Bradley Watmuff, Bruce M. Cohen, Annie Kathuria, Kara Lopez-Lengowski |
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| Rok vydání: | 2019 |
| Předmět: |
Postmortem studies
Cell Adhesion Molecules Neuronal Induced Pluripotent Stem Cells Glutamate decarboxylase Nerve Tissue Proteins Molecular neuroscience Biology Article Antioxidants lcsh:RC321-571 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Neural Stem Cells Interneurons mental disorders medicine Humans Prefrontal cortex lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Cells Cultured Biological Psychiatry 030304 developmental biology Cerebral Cortex 0303 health sciences Gene knockdown medicine.disease Acetylcysteine Psychiatry and Mental health nervous system Schizophrenia Synapses Excitatory postsynaptic potential GABAergic Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Translational Psychiatry, Vol 9, Iss 1, Pp 1-13 (2019) Translational Psychiatry |
| ISSN: | 2158-3188 |
| DOI: | 10.1038/s41398-019-0660-x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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