iPSC-derived homogeneous populations of developing schizophrenia cortical interneurons have compromised mitochondrial function

Abstract

Schizophrenia (SCZ) is a neurodevelopmental disorder. Thus, studying pathogenetic mechanisms underlying SCZ requires studying the development of brain cells. Cortical interneurons (cINs) are consistently observed to be abnormal in SCZ postmortem brains. These abnormalities may explain altered gamma oscillation and cognitive function in patients with SCZ. Of note, currently used antipsychotic drugs ameliorate psychosis, but they are not very effective in reversing cognitive deficits. Characterizing mechanisms of SCZ pathogenesis, especially related to cognitive deficits, may lead to improved treatments. We generated homogeneous populations of developing cINs from 15 healthy control (HC) iPSC lines and 15 SCZ iPSC lines. SCZ cINs, but not SCZ glutamatergic neurons, show dysregulated Oxidative Phosphorylation (OxPhos) related gene expression, accompanied by compromised mitochondrial function. The OxPhos deficit in cINs could be reversed by Alpha Lipoic Acid/Acetyl-L-Carnitine (ALA/ALC) but not by other chemicals previously identified as increasing mitochondrial function. The restoration of mitochondrial function by ALA/ALC was accompanied by a reversal of arborization deficits in SCZ cINs. OxPhos abnormality, even in the absence of any circuit environment with other neuronal subtypes, appears to be an intrinsic deficit in SCZ cINs.

Decreased mitochondrial electron transport proteins and increased complement mediators in plasma neural-derived exosomes of early psychosis

“…The significant decreases in levels of complex I protein in brain tissues of schizophrenic patients have been attributed partially to medications 23 . Nonetheless, induced pluripotent stem cell (iPSC) lines of interneurons from schizophrenic patients showed altered expression of genes encoding proteins involved in numerous mitochondrial activities, including increased generation of ROS 24 . Further there is extensive evidence of increased ROS in schizophrenia and animal models of schizophrenia 25 , 26 .…”

Impairment of methylglyoxal detoxification systems causes mitochondrial dysfunction and schizophrenia-like behavioral deficits

“…Mitochondrial dysfunction has been frequently reported in patients with schizophrenia 36 . Several studies using postmortem brains demonstrated a decrease in the activity of complex IV in the PFC of patients with schizophrenia 37 , and a global down-regulation of mitochondria-related genes by microarray analysis 38 . Also, mitochondrial dysfunction has also been found in patient-derived iPS cells 39,40 ; MG can disrupt mitochondrial respiration 41 .…”

Ketogenic Therapy in Serious Mental Illness: Emerging Evidence

“…These encouraging preclinical data and the emerging evidence from recent case studies certainly support our enthusiasm about the application of ketogenic therapies in serious mental illness, including psychosis ( Sarnyai et al, 2019 ). It is intriguing to speculate about the variety of mechanisms, including the ones reviewed by Morris et al ( Morris et al, 2020 ), as well as others such as mitochondrial Complex 1 and oxidative phosphorylation deficits ( Ben-Shachar, 2017 ; Ni et al, 2019 ) and the role of the gut microbiome ( Olson et al, 2018 ; Zhu et al, 2020 ) through which ketogenic therapies may exert their effect. However, randomized controlled clinical trials are needed to demonstrate the efficacy as well as the safety of this proposed novel treatment approach.…”