NPAS3-regulated astrocyte mitochondrial bioenergetics is required for cognition.
Overview
13 affiliations
- Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
- Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
- Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
- Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Aarhus University, Aarhus, Denmark
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Emotion, Cognition & Behavior Research Group, Korea Brain Research Institute, Daegu, Republic of Korea
- School of Medicine, Kyungpook National University, Daegu, Republic of Korea
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Neurology, Johns Hopkins School of Medicine Baltimore, MD, USA
- Department of Psychiatry, Department of Neurosciences, Department of Pathology, Case Western Reserve University and Institute for Transformative Molecular Medicine, Cleveland, OH, USA
- Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals, Cleveland Medical Center, Cleveland, OH, USA
- Geriatric Psychiatry, GRECC, Louis Stokes VA Medical Center, Cleveland, OH, USA
Abstract
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.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- geo:GSE274921, at NCBI GEO; found in “Data, code, and materials availability:”
Data, code, and materials availability
All data and code needed to evaluate and reproduce the results in the paper are present in the paper and/
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Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 22 authors, 13 MeSH terms, 4 funders, 135 references.
Cite
This paper
Murlanova, K., Novototskaya-Vlasova, K., Huseynov, S., Pletnikova, O., Howell, R. D., Jouroukhin, Y., Kim, D. W., Jenson, A. E.-S., Lee, J., Qin, C., Thompson, S. R., Saraf, V., Morales, M. J., Cortes Gomez, E., Margolis, R. L., Nucifora, F. C., Rosario, S. R., Pieper, A. A., Withers, H. G., . . . Pletnikov, M. V. (2026). NPAS3-regulated astrocyte mitochondrial bioenergetics is required for cognition. Science advances, 12(25), eadt2527. https://
BibTeX
@article{murlanova2026np
author = {Murlanova, Kateryna and Novototskaya-Vlasova, Ksenia and Huseynov, Shovgi and Pletnikova, Olga and Howell, Rebecca D. and Jouroukhin, Yan and Kim, Dong Won and Jenson, Adrian Eddy-Sulaiman and Lee, Juhyun and Qin, Cheng and Thompson, Stephen R. and Saraf, Vikyath and Morales, Michael J. and Cortes Gomez, Eduardo and Margolis, Russell L. and Nucifora, Frederick C. and Rosario, Spencer R. and Pieper, Andrew A. and Withers, Henry G. and Haj-Dahmane, Samir and Kim, Juhyun and Pletnikov, Mikhail V.},
title = {{NPAS3-regulated astrocyte mitochondrial bioenergetics is required for cognition}},
journal = {Science advances},
year = {2026},
month = jun,
volume = {12},
number = {25},
pages = {eadt2527},
publisher = {American Association for the Advancement of Science},
issn = {2375-2548},
doi = {10.1126/
url = {https://
pmid = {42308317},
pmcid = {PMC13274620}
}
RIS
TY - JOUR
AU - Murlanova, Kateryna
AU - Novototskaya-Vlasova, Ksenia
AU - Huseynov, Shovgi
AU - Pletnikova, Olga
AU - Howell, Rebecca D.
AU - Jouroukhin, Yan
AU - Kim, Dong Won
AU - Jenson, Adrian Eddy-Sulaiman
AU - Lee, Juhyun
AU - Qin, Cheng
AU - Thompson, Stephen R.
AU - Saraf, Vikyath
AU - Morales, Michael J.
AU - Cortes Gomez, Eduardo
AU - Margolis, Russell L.
AU - Nucifora, Frederick C.
AU - Rosario, Spencer R.
AU - Pieper, Andrew A.
AU - Withers, Henry G.
AU - Haj-Dahmane, Samir
AU - Kim, Juhyun
AU - Pletnikov, Mikhail V.
TI - NPAS3-regulated astrocyte mitochondrial bioenergetics is required for cognition
T2 - Science advances
J2 - Sci Adv
PY - 2026
DA - 2026/
VL - 12
IS - 25
SP - eadt2527
SN - 2375-2548
PB - American Association for the Advancement of Science
DO - 10.1126/
UR - https://
LA - en
ER -
CSL-JSON
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