NPAS3-regulated astrocyte mitochondrial bioenergetics is required for cognition
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.
Authors
- J D Lee
- Spencer R. Rosario (ORCID: https://orcid.org/0000-0002-2626-9257)
- Henry Withers (ORCID: https://orcid.org/0000-0002-9746-9352)
- Yan Jouroukhin (ORCID: https://orcid.org/0000-0002-5308-1276)
- Kateryna Murlanova (ORCID: https://orcid.org/0000-0001-9236-6648)
- Samir Haj‐Dahmane (ORCID: https://orcid.org/0000-0002-6012-7199)
- Pletnikov Mv
- Michael J. Morales (ORCID: https://orcid.org/0000-0002-1732-2765)
- Eduardo Cortes Gomez (ORCID: https://orcid.org/0000-0002-0966-6488)
- Andrew A. Pieper (ORCID: https://orcid.org/0000-0001-6299-6577)
- Vikyath Saraf
- Shovgi Huseynov (ORCID: https://orcid.org/0000-0002-3663-7236)
- Olga Pletniková (ORCID: https://orcid.org/0000-0001-6516-4944)
- Dong Won Kim (ORCID: https://orcid.org/0000-0001-8624-0168)
- Juhyun Kim (ORCID: https://orcid.org/0000-0002-3098-5010)
- Adrian Lee (ORCID: https://orcid.org/0000-0002-1900-3231)
- Russell L. Margolis (ORCID: https://orcid.org/0000-0003-3024-8595)
- Rebecca Howell (ORCID: https://orcid.org/0000-0002-5332-0791)
- Stephen R. Thompson
- Cheng Qin
- Ksenia Novototskaya-Vlasova
- Frederick C. Nucifora (ORCID: https://orcid.org/0009-0003-1054-0342)
Institutions
- Roswell Park Comprehensive Cancer Center (US)
- Johns Hopkins University (US)
- Aarhus University (DK)
- University Hospitals of Cleveland (US)
- Johns Hopkins Medicine (US)
- Kyungpook National University (KR)
- University Hospitals Cleveland Medical Center (US)
- Louis Stokes Cleveland VA Medical Center (US)
- Korea Brain Research Institute (KR)
- Case Western Reserve University (US)
- University at Buffalo, State University of New York (US)
Publication Details
- Journal
- Science Advances
- Published
- 2026-06-17
- DOI
- https://doi.org/10.1126/sciadv.adt2527
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Korea Brain Research Institute
- National Institute of Mental Health
- National Institute on Drug Abuse
- National Cancer Institute