Wang Xuechun, Li Kuan, Guo Lingzhi, Liu Xinlong, Guo Yatu, Zhang Wei
Clinical College of Ophthalmology, Tianjin Medical University, Tianjin, China.
Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin Eye Hospital, Tianjin, China.
Invest Ophthalmol Vis Sci. 2025 Apr 1;66(4):45. doi: 10.1167/iovs.66.4.45.
To investigate the role of microglial subtypes in mouse visual cortex development, focusing on ocular dominance plasticity and interactions with GABAergic neurons and the extracellular matrix.
Immunofluorescence and single-nucleus RNA-sequencing (snRNA-seq) were used to study microglia in the binocular primary visual cortex (V1) from postnatal day (P) 11 to P42. Gene ontology (GO) analysis assessed synapse organization, and the impact of microglial disruption on ocular dominance plasticity was examined. Visual evoked potentials and miniature postsynaptic current recordings are used to monitor functional changes in V1.
Microglia underwent a marked expansion between P11 and P21 and stabilized after P35, coinciding with notable changes in gene expression that aligned with synaptic remodeling. GO analysis at P14 and P28 revealed significant enrichment in synaptic organization linked to microglia. Single-nucleus RNA sequencing identified six distinct microglial clusters, among which two functionally relevant subpopulations were closely linked to cortical synaptic plasticity. One cluster, enriched in inflammatory responses and endocytosis, peaked at P21, whereas another cluster, associated with synapse organization and signaling, exhibited dynamic changes after eye opening and during the critical period, significantly influencing cortical synaptic plasticity. In parallel, perineuronal nets (PNNs) and PV(+) interneuron populations increased and reached steady levels by P42, suggesting that microglia help coordinate the timing of inhibitory circuit maturation. Disrupting microglial function during the critical period impaired ocular dominance plasticity, but this effect was reversed after treatment cessation. Mechanistically, microglial depletion enhanced PV(+) interneuron numbers, elevated PNN expression, and altered synapse development.
Our findings highlight specific microglial subtypes as key regulators of cortical synapse development and plasticity through their interactions with PV(+) interneurons and PNNs. These insights advance our understanding of microglial contributions to visual cortex development and provide potential avenues for targeting microglial function to modulate cortical plasticity.
研究小胶质细胞亚型在小鼠视觉皮层发育中的作用，重点关注眼优势可塑性以及与γ-氨基丁酸能神经元和细胞外基质的相互作用。
采用免疫荧光和单核RNA测序（snRNA-seq）技术研究出生后第11天（P11）至第42天（P42）小鼠双眼初级视觉皮层（V1）中的小胶质细胞。基因本体（GO）分析评估突触组织，并检测小胶质细胞破坏对眼优势可塑性的影响。使用视觉诱发电位和微小突触后电流记录来监测V1中的功能变化。
小胶质细胞在P11至P21期间显著扩增，并在P35后稳定下来，这与基因表达的显著变化相吻合，这些变化与突触重塑一致。P14和P28的GO分析显示与小胶质细胞相关的突触组织显著富集。单核RNA测序确定了六个不同的小胶质细胞簇，其中两个功能相关的亚群与皮质突触可塑性密切相关。一个簇富含炎症反应和内吞作用，在P21达到峰值，而另一个与突触组织和信号传导相关的簇在睁眼后和关键期表现出动态变化，显著影响皮质突触可塑性。同时，神经元周围网（PNNs）和PV（+）中间神经元群体增加，并在P42达到稳定水平，表明小胶质细胞有助于协调抑制性回路成熟的时间。在关键期破坏小胶质细胞功能会损害眼优势可塑性，但在停止治疗后这种影响会逆转。从机制上讲，小胶质细胞耗竭会增加PV（+）中间神经元数量，提高PNN表达，并改变突触发育。
我们的研究结果突出了特定的小胶质细胞亚型通过与PV（+）中间神经元和PNNs的相互作用，作为皮质突触发育和可塑性的关键调节因子。这些见解增进了我们对小胶质细胞对视觉皮层发育贡献的理解，并为靶向小胶质细胞功能以调节皮质可塑性提供了潜在途径。
