Ju Peijun, Fang Yu, Xiang Siying, Wang Weidi, Sun Ying, Wang Wei, Ding Yanli, Luo Chao, Jiang Ping, Chen Jianhua
Shanghai Institute of Traditional Chinese Medicine for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Clinical Research Center for Mental Health, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
BMC Biol. 2025 Aug 5;23(1):242. doi: 10.1186/s12915-025-02333-5.
Ephrin-B2 (EB2) signaling plays a crucial role in regulating memory and synaptic plasticity. Comprehensive identification of cell-type-specific transcriptomic changes in EB2 knockout mice is expected to shed light on potential mechanisms associated with EB2 signaling in cognitive functions.
Our study captures changes in cell populations in response to EB2 manipulation and reveals previously uncharacterized cell types (CPA6 + inhibitory neurons) in the mPFC. We validated the differential transcriptomic activity of Pbx1 and Meis1 in CPA6 + neurons using fluorescence in situ hybridization (ISH) in EB2-vGATCre mice. The aberrant presence of CPA6 + neurons in the mPFC may correlate with cognitive impairments induced by EB2 deletion in vGAT + neurons. Analyzing differentially expressed genes (DEGs) in individual cell clusters, we identified alterations related to synapse organization and development, cognition, amyloid-beta formation, and locomotor behavior. Additionally, our DEGs overlapped with human genome-wide association study (GWAS) candidate genes related to cognition and anxiety, underscoring the relevance of our mouse model to human disease.
We present a comprehensive atlas of cell-type-specific gene expression changes in this synaptic deficiency model and identify novel cell-type-specific targets implicated in cognitive deficits. Our investigation provides a detailed map of the cell types, genes, and pathways altered in this inhibitory synaptic deficiency model.
Ephrin-B2（EB2）信号传导在调节记忆和突触可塑性中起着至关重要的作用。全面鉴定EB2基因敲除小鼠中细胞类型特异性的转录组变化，有望揭示与EB2信号传导在认知功能中相关的潜在机制。
我们的研究捕捉了细胞群体对EB2操纵的反应变化，并揭示了内侧前额叶皮质中以前未被表征的细胞类型（CPA6+抑制性神经元）。我们在EB2-vGATCre小鼠中使用荧光原位杂交（ISH）验证了Pbx1和Meis1在CPA6+神经元中的差异转录组活性。内侧前额叶皮质中CPA6+神经元的异常存在可能与vGAT+神经元中EB2缺失诱导的认知障碍相关。通过分析各个细胞簇中的差异表达基因（DEG），我们确定了与突触组织和发育、认知、淀粉样β蛋白形成以及运动行为相关的改变。此外，我们的DEG与人类全基因组关联研究（GWAS）中与认知和焦虑相关的候选基因重叠，强调了我们的小鼠模型与人类疾病的相关性。
我们展示了这个突触缺陷模型中细胞类型特异性基因表达变化的综合图谱，并确定了与认知缺陷相关的新型细胞类型特异性靶点。我们的研究提供了这个抑制性突触缺陷模型中细胞类型、基因和通路改变的详细图谱。
