Stra8 links neuronal activity to inhibitory circuit protection in the adult mouse brain.

Creator(s)

Ming Huang
Shuwen Yue
Xiaoyu Zhang
Lan Wu
Jay L. Vivian, Children's Mercy HospitalFollow
Zi-Jun Wang
Ning Wang

Document Type

Article

Publication Date

11-25-2025

Identifier

DOI: 10.1016/j.celrep.2025.116513; PMCID: PMC12736790

Abstract

While neuronal activity is essential for brain function, it also poses threats to neuronal integrity. Here, we show that activity-induced expression of stimulated by retinoic acid gene 8 (Stra8) protects neurons from degeneration. Previously considered germline specific, Stra8 is expressed in the adult mouse brain and is induced by neuronal activity via calcium influx and N-methyl-D-aspartate (NMDA) receptor signaling. Neuron-specific Stra8 knockout mice display hallmark features of neurodegeneration, including DNA damage, impaired proteostasis, inflammation, nuclear envelope erosion, reduced dendritic plasticity, memory deficits, and heightened excitotoxic vulnerability. Electrophysiological studies reveal disrupted inhibitory circuit function. Mechanistically, Stra8 binds regulatory regions of neuromodulator genes and regulates their expression. Notably, Stra8 loss upregulates the expression of Npas4, an immediate-early gene critical for inhibitory circuits, but the aberrant protein is mislocalized to the nuclear periphery. These findings identify Stra8 as an activity-dependent transcriptional regulator that safeguards neuronal structure and function.

Journal Title

Cell Rep

Volume

44

Issue

11

First Page

116513

Last Page

116513

MeSH Keywords

Animals; Neurons; Mice; Brain; Mice, Knockout; Basic Helix-Loop-Helix Transcription Factors; Adaptor Proteins, Signal Transducing; Receptors, N-Methyl-D-Aspartate; Mice, Inbred C57BL; Neuronal Plasticity

PubMed ID

41187062

Keywords

CP: Neuroscience; Npas4; Stra8; cognitive function; hippocampus; inhibitory neurons; neural circuits; neurodegeneration; transcriptional regulation

Comments

Grants and funding

• P30 GM122731/GM/NIGMS NIH HHS/United States
• R01 HD103888/HD/NICHD NIH HHS/United States
• P30 CA168524/CA/NCI NIH HHS/United States
• P30 AG072973/AG/NIA NIH HHS/United States
• U54 HD090216/HD/NICHD NIH HHS/United States
• S10 OD036343/OD/NIH HHS/United States
• UL1 TR002366/TR/NCATS NIH HHS/United States

This article is available under the Creative Commons CC-BY-NC license and permits non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.

Publisher's Link: https://doi.org/10.1016/j.celrep.2025.116513

Recommended Citation

Huang M, Yue S, Zhang X, et al. Stra8 links neuronal activity to inhibitory circuit protection in the adult mouse brain. Cell Rep. 2025;44(11):116513. doi:10.1016/j.celrep.2025.116513