DISC1 regulates lactate metabolism in astrocytes: Implications for psychiatric disorders. / Jouroukhin, Yan; Kageyama, Yusuke; Misheneva, Varvara et al.
In: Translational Psychiatry, Vol. 8, No. 1, 76, 01.12.2018.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - DISC1 regulates lactate metabolism in astrocytes: Implications for psychiatric disorders
AU - Jouroukhin, Yan
AU - Kageyama, Yusuke
AU - Misheneva, Varvara
AU - Shevelkin, Alexey
AU - Andrabi, Shaida
AU - Prandovszky, Emese
AU - Yolken, Robert H.
AU - Dawson, Valina L.
AU - Dawson, Ted M.
AU - Aja, Susan
AU - Sesaki, Hiromi
AU - Pletnikov, Mikhail V.
N1 - Funding Information: This work was supported by MH-083728, MH-094268 the Conte Center grant, and The Brain and Behavior Research Foundation (MVP), DA00266 and NSR37 NS067525 (TMD and VLD). The authors also thank Mr. Glen Hatfield for his expert help with qRT-PCR experiments. Funding:The authors declare no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
KW - Animals
KW - Astrocytes/metabolism
KW - Behavior, Animal
KW - Energy Metabolism
KW - Gene Knockdown Techniques
KW - Glucose/metabolism
KW - Humans
KW - Lactic Acid/metabolism
KW - Membrane Potential, Mitochondrial
KW - Mental Disorders/genetics
KW - Mice
KW - Mice, Transgenic
KW - Nerve Tissue Proteins/genetics
UR - http://www.scopus.com/inward/record.url?scp=85045253481&partnerID=8YFLogxK
UR - https://elibrary.ru/item.asp?id=35543522
U2 - 10.1038/s41398-018-0123-9
DO - 10.1038/s41398-018-0123-9
M3 - Article
C2 - 29643356
AN - SCOPUS:85045253481
VL - 8
JO - Translational Psychiatry
JF - Translational Psychiatry
SN - 2158-3188
IS - 1
M1 - 76
ER -
ID: 41268201