麻省理工学院和哈佛大学的布罗德研究所Gord Fishell小组近日取得一项新成果。经过不懈努力，他们发现锥体神经元按比例改变皮层中间神经元亚型。2026年1月21日出版的《自然》杂志发表了这项成果。

本研究表明，锥体神经元通过促进相关中间神经元亚型的存活和终末分化，在这一过程中发挥了积极作用。在野生型皮层中，中间神经元亚型的丰度反映了其锥体神经元伙伴的流行。在Fezf2突变体中，缺乏L5b锥体神经元并在L6脑外神经元中扩增，相应的亚型特异性转变通过两种不同的机制发生：生长抑素中间神经元调整其程序性细胞死亡，而小白蛋白中间神经元改变其亚型身份。沉默L5b锥体神经元的神经元活动或阻断囊泡释放表明，它们与中间神经元的交流不需要电压门控制的突触活动，而是同时参与破伤风毒素敏感和破伤风毒素不敏感的途径。

此外，对Fezf2突变体中显示亚型特异性表达和锥体神经元源性配体表达减少的配体-受体对进行了靶向生物信息学筛选，确定了候选分泌因子和粘附分子。这些发现揭示了独特的锥体神经元驱动机制雕刻中间神经元多样性并将其整合到局部皮层回路中。

研究人员表示，哺乳动物大脑皮层由复杂的神经元网络组成，在兴奋性锥体神经元和抑制性中间神经元之间保持精确的平衡。越来越多的证据表明，特定的中间神经元亚型形成了具有不同锥体神经元类别的定型微电路。

附：英文原文

Title: Pyramidal neurons proportionately alter cortical interneuron subtypes

Author: Wu, Sherry Jingjing, Dai, Min, Yang, Shang-Po, McCann, Cai, Qiu, Yanjie, Kumar, Vipin, Marrero, Giovanni J., Tsyporin, Jeremiah, Huang, Shuhan, Shin, David, Stogsdill, Jeffrey A., Di Bella, Daniela J., Xu, Qing, Chen, Bin, Farhi, Samouil L., Macosko, Evan Z., Chen, Fei, Fishell, Gord

Issue&Volume: 2026-01-21

Abstract: The mammalian cerebral cortex comprises a complex neuronal network that maintains a precise balance between excitatory pyramidal neurons and inhibitory interneurons. Accumulating evidence indicates that specific interneuron subtypes form stereotyped microcircuits with distinct pyramidal neuron classes1,2,3. Here we show that pyramidal neurons have an active role in this process by promoting the survival and terminal differentiation of their associated interneuron subtypes. In the wild-type cortex, interneuron subtype abundance mirrors the prevalence of their pyramidal neuron partners. In Fezf2 mutants, which lack L5b pyramidal neurons and are expanded in L6 intratelencephalic neurons, corresponding subtype-specific shifts occur through two distinct mechanisms: somatostatin interneurons adjust their programmed cell death, whereas parvalbumin interneurons switch their subtype identity. Silencing neuronal activity or blocking vesicular release in L5b pyramidal neurons revealed that their communication with interneurons does not require voltage-gated synaptic activity but engages both tetanus toxin-sensitive and tetanus toxin-insensitive pathways. Moreover, a targeted bioinformatic screen for ligand–receptor pairs displaying subtype-specific expression and reduced expression of pyramidal neuron-derived ligand in Fezf2 mutants identified candidate secreted factors and adhesion molecules. These findings reveal distinct, pyramidal neuron-driven mechanisms for sculpting interneuron diversity and integrating them into local cortical circuits.

DOI: 10.1038/s41586-025-09996-8

Source: https://www.nature.com/articles/s41586-025-09996-8