1. Activated microglia cause metabolic disruptions in developmental cortical interneurons that persist in interneurons from individuals with schizophrenia
- Author
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Donna L. McPhie, Hae-Young Kim, Gun-Hoo Park, Peiyan Ni, Yiren Qin, Sangmi Chung, Joseph T. Coyle, Zhicheng Shao, Derek T Le, James M. Park, Haneul Noh, Chiderah P Abani, Weihua Huang, Hualin S. Xi, Dongxin Liu, Changhong Yin, Joy S. Park, Cameron P Beaudreault, Bruce M. Cohen, Sasha Z Gonzalez, Thomas A. Lanz, and Youxin Guan
- Subjects
Adult ,Male ,0301 basic medicine ,Induced Pluripotent Stem Cells ,Gene Expression ,Glutamic Acid ,Biology ,Article ,Transcriptome ,Young Adult ,03 medical and health sciences ,Glutamatergic ,0302 clinical medicine ,Immune system ,Interneurons ,Gene expression ,medicine ,Humans ,Induced pluripotent stem cell ,gamma-Aminobutyric Acid ,Cerebral Cortex ,Microglia ,General Neuroscience ,Middle Aged ,medicine.disease ,Coculture Techniques ,Mitochondria ,Metabolic pathway ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Schizophrenia ,Encephalitis ,Neuroscience ,030217 neurology & neurosurgery - Abstract
The mechanisms by which prenatal immune activation increase the risk for neuropsychiatric disorders are unclear. Here, we generated developmental cortical interneurons (cINs)-which are known to be affected in schizophrenia (SCZ) when matured-from induced pluripotent stem cells (iPSCs) derived from healthy controls (HCs) and individuals with SCZ and co-cultured them with or without activated microglia. Co-culture with activated microglia disturbed metabolic pathways, as indicated by unbiased transcriptome analyses, and impaired mitochondrial function, arborization, synapse formation and synaptic GABA release. Deficits in mitochondrial function and arborization were reversed by alpha lipoic acid and acetyl-L-carnitine treatments, which boost mitochondrial function. Notably, activated-microglia-conditioned medium altered metabolism in cINs and iPSCs from HCs but not in iPSCs from individuals with SCZ or in glutamatergic neurons. After removal of activated-microglia-conditioned medium, SCZ cINs but not HC cINs showed prolonged metabolic deficits, which suggests that there is an interaction between SCZ genetic backgrounds and environmental risk factors.
- Published
- 2020
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