TY - JOUR
T1 - NPAS3-Regulated Astrocyte Mitochondrial Bioenergetics is Required for Cognition
AU - Murlanova, Kateryna
AU - Novototskaya-Vlasova, Ksenia
AU - Huseynov, Shovgi
AU - Pletnikova, Olga
AU - Howell, Rebecca
AU - Jouroukhin, Yan
AU - Kim, Dong Won
AU - Eddy-Sulaiman Jenson, Adrian
AU - Lee, Juhyun
AU - Cheng, Qin
AU - Thompson, Stephen
AU - Saraf, Vikyath
AU - Morales, Michael
AU - Gomez, Eduardo Cortes
AU - Margolis, Russell
AU - Nucifora, Frederick
AU - Rosario, Spencer
AU - Pieper, Andrew
AU - Withers, Henry
AU - Haj-Dahmane, Samir
AU - Juhyun, Kim
AU - Pletnikov, Mikhail
N1 - Publisher Copyright:
© 2026 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
PY - 2026
Y1 - 2026
N2 - The basic helix-loop-helix transcription factor neuronal PAS (Per, Arnt, Sim) domain protein 3 (NPAS3) provides transcriptional regulation of metabolic pathways and is highly expressed in astrocytes. NPAS3 variants have been associated with cognitive dysfunction under several neuropsychiatric conditions, but the underlying brain cell type–specific mechanisms remain obscure. Here, we report that NPAS3 is a key regulator of mitochondrial bioenergetics in astrocytes in the mouse brain. Selective deletion of Npas3 in mature astrocytes decreases expression of mitochondrial glutamate carrier 2 involved in glutamate oxidation, leading to reduced oxidative phosphorylation and lactate production in astrocytes. This deficit reduces intrinsic excitability, dendritic spine density, and excitatory synaptic transmission of medial prefrontal cortex (mPFC) pyramidal neurons. Mice with Npas3-deficient mPFC astrocytes exhibit impaired trace fear conditioning, which is rescued by lactate treatment. Thus, the present study demonstrates a mechanistic link between NPAS3-dependent astrocyte mitochondrial bioenergetics and cognitive function and provides insights for glia-targeting treatment of cognitive dysfunction in neuropsychiatric disease.
AB - The basic helix-loop-helix transcription factor neuronal PAS (Per, Arnt, Sim) domain protein 3 (NPAS3) provides transcriptional regulation of metabolic pathways and is highly expressed in astrocytes. NPAS3 variants have been associated with cognitive dysfunction under several neuropsychiatric conditions, but the underlying brain cell type–specific mechanisms remain obscure. Here, we report that NPAS3 is a key regulator of mitochondrial bioenergetics in astrocytes in the mouse brain. Selective deletion of Npas3 in mature astrocytes decreases expression of mitochondrial glutamate carrier 2 involved in glutamate oxidation, leading to reduced oxidative phosphorylation and lactate production in astrocytes. This deficit reduces intrinsic excitability, dendritic spine density, and excitatory synaptic transmission of medial prefrontal cortex (mPFC) pyramidal neurons. Mice with Npas3-deficient mPFC astrocytes exhibit impaired trace fear conditioning, which is rescued by lactate treatment. Thus, the present study demonstrates a mechanistic link between NPAS3-dependent astrocyte mitochondrial bioenergetics and cognitive function and provides insights for glia-targeting treatment of cognitive dysfunction in neuropsychiatric disease.
UR - https://www.scopus.com/pages/publications/105043124183
U2 - 10.1126/sciadv.adt2527
DO - 10.1126/sciadv.adt2527
M3 - Article
C2 - 42308317
AN - SCOPUS:105043124183
SN - 2375-2548
VL - 12
JO - Science Advances
JF - Science Advances
IS - 25
M1 - eadt2527
ER -