BMC biology · 2025
Ephrin-B2 deletion in GABAergic neurons induces cognitive deficits associated with single-nucleus transcriptomic differences in the prefrontal cortex.
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Ju Peijun, Fang Yu, Xiang Siying, Wang Weidi, Sun Ying, Wang Wei, Ding Yanli, Luo Chao, Jiang Ping, Chen Jianhua
Аннотация
BACKGROUND: 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.
RESULTS: 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.
CONCLUSIONS: 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.
RESULTS: 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.
CONCLUSIONS: 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.