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Background <p>Dysregulated stress responses are increasingly implicated in the pathophysiology of autism spectrum disorder (ASD). Astrocytes, which are highly vulnerable to stress, critically support neuronal survival; however, their specific role in ASD remains poorly defined.</p> Methods <p>We analyzed single nucleus RNA sequencing data from postmortem cortices of ASD and control donors. Our analysis included enrichment analysis of astrocyte subpopulations and integrated pySCENIC-based GRN reconstruction, TF profiling, regulon-DEG analysis, and cell-cell communication. Mechanistic studies involved human iPSC-derived astrocytes-neurons co-culture and astrocyte-specific <i>JUND</i> overexpression in mice. Functional and behavioral assessments were performed to evaluate neuronal viability and ASD-relevant phenotypes.</p> Results <p>A subpopulation of stress-responsive astrocytes (SRAs) was identified as specifically enriched in ASD, displaying early transcriptional activation and increased abundance. These SRAs showed marked upregulation of both stress-response pathways and distinct reactive signatures. JUND was established as the core transcriptional orchestrator, controlling 23.8% of the dysregulated transcriptome that defines the core stress-responsive signature, including multiple ASD risk genes. <i>JUND</i> overexpression in astrocytes recapitulated the SRAs molecular profile, while astrocyte-specific JUND activation in mouse cortex elicited core ASD-like behaviors. Mechanistically, JUND upregulated the gap junction gene <i>GJA1</i>, enhancing astrocyte-neuron communication and promoting neuronal apoptosis. This pathogenic cascade was rescued by the gap junction inhibitor GAP27.</p> Limitations <p>This study is focused solely on specific brain regions, the generalizability of the JUND-GJA1-GAP axis across diverse ASD subtypes remains to be validated, and the complete activation pathway of JUND signaling within SRAs as well as their interaction mechanisms with other glial cells are not well understood.</p> Conclusions <p>Our findings demonstrate that a specialized astrocyte subpopulation mediates stress-induced dysfunction in ASD via a JUND-GJA1-GAP apoptotic signaling axis, providing a translational anchor for targeting astrocyte-specific pathways in ASD therapy.</p>

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JUND-driven stress-responsive astrocytes promote neuronal apoptosis via enhanced gap junction signaling in autism spectrum disorder

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月19日

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  • Qi Wang,
  • Huamin Yin,
  • Qi Jiang,
  • Yubo Qi,
  • Jieli Bai,
  • Zhendong Wang,
  • Kailai Liu,
  • Ruizhen Sun,
  • Wenhang Wang,
  • Canying Liu,
  • Weishuo Yan,
  • Jin Luo,
  • Lian Duan,
  • Zhiyan Shan

摘要

Background

Dysregulated stress responses are increasingly implicated in the pathophysiology of autism spectrum disorder (ASD). Astrocytes, which are highly vulnerable to stress, critically support neuronal survival; however, their specific role in ASD remains poorly defined.

Methods

We analyzed single nucleus RNA sequencing data from postmortem cortices of ASD and control donors. Our analysis included enrichment analysis of astrocyte subpopulations and integrated pySCENIC-based GRN reconstruction, TF profiling, regulon-DEG analysis, and cell-cell communication. Mechanistic studies involved human iPSC-derived astrocytes-neurons co-culture and astrocyte-specific JUND overexpression in mice. Functional and behavioral assessments were performed to evaluate neuronal viability and ASD-relevant phenotypes.

Results

A subpopulation of stress-responsive astrocytes (SRAs) was identified as specifically enriched in ASD, displaying early transcriptional activation and increased abundance. These SRAs showed marked upregulation of both stress-response pathways and distinct reactive signatures. JUND was established as the core transcriptional orchestrator, controlling 23.8% of the dysregulated transcriptome that defines the core stress-responsive signature, including multiple ASD risk genes. JUND overexpression in astrocytes recapitulated the SRAs molecular profile, while astrocyte-specific JUND activation in mouse cortex elicited core ASD-like behaviors. Mechanistically, JUND upregulated the gap junction gene GJA1, enhancing astrocyte-neuron communication and promoting neuronal apoptosis. This pathogenic cascade was rescued by the gap junction inhibitor GAP27.

Limitations

This study is focused solely on specific brain regions, the generalizability of the JUND-GJA1-GAP axis across diverse ASD subtypes remains to be validated, and the complete activation pathway of JUND signaling within SRAs as well as their interaction mechanisms with other glial cells are not well understood.

Conclusions

Our findings demonstrate that a specialized astrocyte subpopulation mediates stress-induced dysfunction in ASD via a JUND-GJA1-GAP apoptotic signaling axis, providing a translational anchor for targeting astrocyte-specific pathways in ASD therapy.