Abstract
Our knowledge of how genetic risk variants contribute to psychiatric disease is mainly limited to neurons. However, the mechanisms whereby the same genetic risk factors could affect the physiology of glial cells remain poorly understood. We studied the role of a psychiatric genetic risk factor, Disrupted-In-Schizophrenia-1 (DISC1), in metabolic functions of astrocytes. We evaluated the effects of knockdown of mouse endogenous DISC1 (DISC1-KD) and expression of a dominant-negative, C-terminus truncated human DISC1 (DN-DISC1) on the markers of energy metabolism, including glucose uptake and lactate production, in primary astrocytes and in mice with selective expression of DN-DISC1 in astrocytes. We also assessed the effects of lactate treatment on altered affective behaviors and impaired spatial memory in DN-DISC1 mice. Both DISC1-KD and DN-DISC1 comparably decreased mRNA and protein levels of glucose transporter 4 and glucose uptake by primary astrocytes. Decreased glucose uptake was associated with reduced oxidative phosphorylation and glycolysis as well as diminished lactate production in vitro and in vivo. No significant effects of DISC1 manipulations in astrocytes were observed on expression of the subunits of the electron transport chain complexes or mitofilin, a neuronal DISC1 partner. Lactate treatment rescued the abnormal behaviors in DN-DISC1 male and female mice. Our results suggest that DISC1 may be involved in the regulation of lactate production in astrocytes to support neuronal activity and associated behaviors. Abnormal expression of DISC1 in astrocytes and resulting abnormalities in energy supply may be responsible for aspects of mood and cognitive disorders observed in patients with major psychiatric illnesses.
Highlights
Astrocytes are the most abundant cells in the brain, and pathological changes in astrocytes are likely to contribute to cognitive impairment and behavioral disorders[1,2]
Two-way repeated measures analyses of variance (ANOVA) revealed a significant effect of KD, F(1, 23) = 101,69, P < 0.01; a post hoc Bonferroni test showed that basal respiration (P < 0.05) and the maximal respiration rate measured after CCCP injection (P < 0.05) were significantly lower in DISC1-KD astrocytes than in control astrocytes; * p < 0.05. b extracellular acidification rate (ECAR) for control and DISC1-KD primary astrocytes; n = 5 independent cultures; each culture was measured in duplicate, and each experiment was repeated at least three times
Two-way repeated measures ANOVA revealed a significant effect of KD, F(1, 23) = 175.7, p < 0.01; a post hoc Bonferroni test showed that basal glycolysis (P < 0.05) and glycolytic capacity measured after oligomycin injection (P < 0.01) were significantly lower in DISC1-KD astrocytes than in control astrocytes; * p < 0.05, **p < 0.01
Summary
Astrocytes are the most abundant cells in the brain, and pathological changes in astrocytes are likely to contribute to cognitive impairment and behavioral disorders[1,2]. Our understanding of the underlying molecular mechanisms is limited to neurons, and little is known of the pathogenic contributions of genetic risk factors within glia, including astrocytes[7,8]. DISC1 has not been associated with schizophrenia in the latest genome-wide association studies (GWAS)[10] and is likely a general psychiatric risk factor that may be involved in the molecular pathogenesis of several neuropsychiatric disorders. As a genetic element of the highly penetrant ultrarare chromosomal translocation, DISC1 and its protein products could be used as valuable molecular tools for mechanistic studies to advance our understanding of the molecular pathobiology of several major psychiatric diseases, irrespective of their categorical classifications[11]
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