Evidence map›Paper›PMID 42700720›Full record

ArticleEBioMedicine2026

ERK-dependent hyperexcitability of BLA neurons projecting to dCA3 underlies social dysfunction in a male mouse model of fragile X syndrome.

Siyu Wang, Xiaotong Wu, Siyuan Dong, Lu Zheng, Libiao Pan, Li Zhan, Hanyang Xiao, Li Yang, Xiaomeng Wang, Huan Ma and 4 more

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Article in EBioMedicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 · Who and what money

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14 authors.

Siyu WangDepartment of Neurosurgery of Second Affiliated Hospital and School of Brain Science and Brain Medicine, Key Laboratory for Biomedical Engineering of Education Ministry, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China; Nanhu Brain-computer Interface Institute, Hangzhou, 311100, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Centre for Brain Research and Brain Machine Integration, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
Xiaotong WuDepartment of Neurosurgery of Second Affiliated Hospital and School of Brain Science and Brain Medicine, Key Laboratory for Biomedical Engineering of Education Ministry, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China; Nanhu Brain-computer Interface Institute, Hangzhou, 311100, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Centre for Brain Research and Brain Machine Integration, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
Siyuan DongDepartment of Gastroenterology, Ningbo Medical Centre LiHuiLi Hospital, Ningbo, Zhejiang, 315000, China.
Lu ZhengDepartment of Neurosurgery of Second Affiliated Hospital and School of Brain Science and Brain Medicine, Key Laboratory for Biomedical Engineering of Education Ministry, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Centre for Brain Research and Brain Machine Integration, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
Libiao PanDepartment of Neurosurgery of Second Affiliated Hospital and School of Brain Science and Brain Medicine, Key Laboratory for Biomedical Engineering of Education Ministry, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Centre for Brain Research and Brain Machine Integration, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
Li ZhanDepartment of Neurosurgery of Second Affiliated Hospital and School of Brain Science and Brain Medicine, Key Laboratory for Biomedical Engineering of Education Ministry, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Centre for Brain Research and Brain Machine Integration, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
Hanyang XiaoDepartment of Neurosurgery of Second Affiliated Hospital and School of Brain Science and Brain Medicine, Key Laboratory for Biomedical Engineering of Education Ministry, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Centre for Brain Research and Brain Machine Integration, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
Li YangDepartment of Neurosurgery of Second Affiliated Hospital and School of Brain Science and Brain Medicine, Key Laboratory for Biomedical Engineering of Education Ministry, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Centre for Brain Research and Brain Machine Integration, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
Xiaomeng WangDepartment of Neurosurgery of Second Affiliated Hospital and School of Brain Science and Brain Medicine, Key Laboratory for Biomedical Engineering of Education Ministry, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China; Nanhu Brain-computer Interface Institute, Hangzhou, 311100, China.
Huan MaDepartment of Neurosurgery of Second Affiliated Hospital and School of Brain Science and Brain Medicine, Key Laboratory for Biomedical Engineering of Education Ministry, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Centre for Brain Research and Brain Machine Integration, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
Han XuDepartment of Neurosurgery of Second Affiliated Hospital and School of Brain Science and Brain Medicine, Key Laboratory for Biomedical Engineering of Education Ministry, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China; Nanhu Brain-computer Interface Institute, Hangzhou, 311100, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Centre for Brain Research and Brain Machine Integration, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
Bingxing PanInstitute of Biomedical Innovation, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330027, China.
Lang WangInterdisciplinary Institute of Neuroscience and Technology, Zhejiang University School of Medicine, Hangzhou, 310027, China.
Hao WangDepartment of Neurosurgery of Second Affiliated Hospital and School of Brain Science and Brain Medicine, Key Laboratory for Biomedical Engineering of Education Ministry, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China; Nanhu Brain-computer Interface Institute, Hangzhou, 311100, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Centre for Brain Research and Brain Machine Integration, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China; Lingang Laboratory, Shanghai, 200031, China. Electronic address: haowang@zju.edu.cn.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundSocial dysfunction is a core symptom of autism spectrum disorder (ASD), including fragile X syndrome (FXS), but its underlying neural circuits and molecular mechanisms remain poorly understood. Previous studies have implicated the amygdala and hippocampus in social behaviour, yet the specific pathways and signalling events linking genetic deficits to behavioural dysfunction have not been fully delineated.

methodsUsing activity-dependent c-Fos mapping, fibre photometry, closed-loop optogenetics, pharmacological inhibition, and shRNA-mediated knockdown, we investigated the role of the BLA-dCA3 projection and ERK signalling in male Fmr1 KO mice, complemented by re-analysis of human ASD snRNA-seq data and whole-cell patch-clamp recordings.

findingsWe found that BLA-dCA3 projecting neurons are aberrantly hyperactivated in Fmr1 KO mice during interactions with both novel and familiar mice, and that closed-loop activation of this pathway in WT mice during familiar interaction impairs social discrimination, whereas its inhibition in KO mice rescues the deficit. Additionally, ERK signalling is upregulated in the BLA of both patients with ASD and Fmr1 KO mice; knocking down FMR1 in the adult BLA recapitulates both the social deficit and ERK hyperactivation, while pharmacological ERK inhibition rescues social behaviour and normalises neuronal hyperexcitability.

interpretationThese findings pinpoint the BLA-dCA3 circuit and BLA-specific ERK signalling as critical mediators of social discrimination deficits in FXS. Our study establishes a causal link from FMRP loss to circuit dysfunction and ERK pathway dysregulation, and suggests that targeting this pathway may offer a promising strategy for treating social dysfunction in ASD and FXS.

fundingThis work was supported by grants from the National Science and Technology Major Project (2025ZD0214701), the National Natural Science Foundation of China (32171014, 31970940, and 32500889), Nanhu Brain-Computer Interface Institute (010904018), and the Zhejiang Provincial Natural Science Foundation of China (LMS25C090004).

Indexed as

ASDERK signalling pathwayFmr1Social dysfunctionThe BLA

Identifiers

PMID42700720
PMCPMC13572171

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