Wu Sherry Jingjing, Dai Min, Yang Shang-Po, McCann Cai, Qiu Yanjie, Marrero Giovanni J, Stogsdill Jeffrey A, Di Bella Daniela J, Xu Qing, Farhi Samouil L, Macosko Evan Z, Che Fei, Fishell Gord
Harvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Res Sq. 2024 Aug 2:rs.3.rs-4774421. doi: 10.21203/rs.3.rs-4774421/v1.
The mammalian cerebral cortex comprises a complex neuronal network that maintains a delicate balance between excitatory neurons and inhibitory interneurons. Previous studies, including our own research, have shown that specific interneuron subtypes are closely associated with particular pyramidal neuron types, forming stereotyped local inhibitory microcircuits. However, the developmental processes that establish these precise networks are not well understood. Here we show that pyramidal neuron types are instrumental in driving the terminal differentiation and maintaining the survival of specific associated interneuron subtypes. In a wild-type cortex, the relative abundance of different interneuron subtypes aligns precisely with the pyramidal neuron types to which they synaptically target. In mutant cortex, characterized by the absence of layer 5 pyramidal tract neurons and an expansion of layer 6 intratelencephalic neurons, we observed a corresponding decrease in associated layer 5b interneurons and an increase in layer 6 subtypes. Interestingly, these shifts in composition are achieved through mechanisms specific to different interneuron types. While SST interneurons adjust their abundance to the change in pyramidal neuron prevalence through the regulation of programmed cell death, parvalbumin interneurons alter their identity. These findings illustrate two key strategies by which the dynamic interplay between pyramidal neurons and interneurons allows local microcircuits to be sculpted precisely. These insights underscore the precise roles of extrinsic signals from pyramidal cells in the establishment of interneuron diversity and their subsequent integration into local cortical microcircuits.
哺乳动物的大脑皮层由一个复杂的神经元网络组成，该网络在兴奋性神经元和抑制性中间神经元之间维持着微妙的平衡。包括我们自己的研究在内，以往的研究表明，特定的中间神经元亚型与特定的锥体神经元类型密切相关，形成了刻板的局部抑制性微电路。然而，建立这些精确网络的发育过程尚未得到很好的理解。在这里，我们表明锥体神经元类型在驱动特定相关中间神经元亚型的终末分化和维持其存活方面发挥着重要作用。在野生型皮层中，不同中间神经元亚型的相对丰度与它们突触靶向的锥体神经元类型精确对齐。在以第5层锥体束神经元缺失和第6层脑内神经元扩张为特征的突变皮层中，我们观察到相关的第5b层中间神经元相应减少，第6层亚型增加。有趣的是，这些组成上的变化是通过不同中间神经元类型特有的机制实现的。虽然SST中间神经元通过程序性细胞死亡的调节来调整其丰度以适应锥体神经元患病率的变化，但小白蛋白中间神经元会改变其身份。这些发现说明了锥体神经元和中间神经元之间的动态相互作用使局部微电路得以精确塑造的两个关键策略。这些见解强调了来自锥体细胞的外在信号在中间神经元多样性建立及其随后整合到局部皮层微电路中的精确作用。
