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 -