Author Correction: A human-specific modifier of cortical connectivity and circuit function
Author Correction: A human-specific modifier of cortical connectivity and circuit function
复制标题
作者更正：皮质连接和电路功能的人类特异性修饰剂
DOI：
10.1038/s41586-021-04302-8
复制
发表时间：
2022
期刊：
影响因子：
64.8
通讯作者：
Miller, Kenneth D.
中科院分区：
文献类型：
--
作者：
Schmidt, Ewoud R.;Zhao, Hanzhi T.;Park, Jung M.;Dipoppa, Mario;Monsalve-Mercado, Mauro M.;Dahan, Jacob B.;Rodgers, Chris C.;Lejeune, Amélie;Hillman, Elizabeth M.;Miller, Kenneth D.
人类特有的认知能力被认为来自人类大脑皮层回路结构的独特特征，包括增加的皮层-皮层连接。然而，这些连接变化的进化起源以及它们如何影响皮质回路功能和行为目前尚不清楚。人类特异性基因重复SRGAP 2C出现在祖先基因组的同源系之前的主要阶段，在脑大小的增加1，2。小鼠中的SRGAP 2C表达增加由第2/3层锥体神经元（PN）接收的兴奋性和抑制性突触的密度3-5。在这里，我们表明，SRGAP 2C表达诱导的第2/3层PN接收的兴奋性突触的数量增加源于局部和远程皮质-皮质连接的特定增加。在所有皮质PN中表达SRGAP 2C的人源化小鼠显示由感觉刺激激活的第2/3层PN的分数的转变和学习皮质依赖性感觉辨别任务的增强能力。计算模型显示，SRGAP 2C表达诱导的第4层到第2/3层连接性的增加解释了感觉编码特性的一些关键变化。这些结果表明，SRGAP 2Cat的出现和Homolineage的诞生促进了人类皮层中皮层回路的特定结构和功能特征的进化。近年来，越来越多的人类特异性遗传修饰物被鉴定出来，例如人类特异性基因重复6，7，它们可以诱导人类特异性的大脑发育特征。这一想法的第一个实验测试来自于对人类特异性基因复制影响祖先基因Slit-Robo GT3激活蛋白2A（SRGAP 2A）的研究。SRGAP 2A在人类谱系中的特异性复制导致了人类特异性旁系同源物SRGAP 2C 3、4的出现。当在小鼠皮质PN体内表达时，SRGAP 2C抑制祖先SRGAP 2A的功能，SRGAP 2A是一种突触后蛋白，调节皮质PN中的兴奋性和抑制性突触成熟和密度。由于其F-BAR结构域的最后49个氨基酸的截短，SRGAP 2C本质上是不稳定的，但仍然能够与SRGAP 2A的F-BAR结构域二聚化，从而通过蛋白酶体依赖性降解降低SRGAP 2A水平5，8。人特异性SRGAP 2C在小鼠2/3层PN中的表达诱导突触发育的变化，其表型复制SRGAP 2A功能的部分丧失并模仿表征人皮质PN的突触特征。这些包括由第2/3层PN接收的兴奋性和抑制性突触的密度的类似增加以及兴奋性和抑制性突触发育的幼态特征3-5。这些发现表明，表达SRGAP 2C的小鼠皮质PN接受突触输入的数量增加，类似于在人PN中观察到的情况9，10。因此，SRGAP 2C可以作为人类大脑皮层连接的人类特异性修饰剂。
The cognitive abilities that characterize humans are thought to emerge from unique features of the cortical circuit architecture of the human brain, which include increased cortico–cortical connectivity. However, the evolutionary origin of these changes in connectivity and how they affected cortical circuit function and behaviour are currently unknown. The human-specific gene duplication SRGAP2Cemerged in the ancestral genome of the Homolineage before the major phase of increase in brain size 1, 2. SRGAP2C expression in mice increases the density of excitatory and inhibitory synapses received by layer 2/3 pyramidal neurons (PNs) 3–5. Here we show that the increased number of excitatory synapses received by layer 2/3 PNs induced by SRGAP2C expression originates from a specific increase in local and long-range cortico–cortical connections. Mice humanized for SRGAP2C expression in all cortical PNs displayed a shift in the fraction of layer 2/3 PNs activated by sensory stimulation and an enhanced ability to learn a cortex-dependent sensory-discrimination task. Computational modelling revealed that the increased layer 4 to layer 2/3 connectivity induced by SRGAP2C expression explains some of the key changes in sensory coding properties. These results suggest that the emergence of SRGAP2Cat the birth of the Homolineage contributed to the evolution of specific structural and functional features of cortical circuits in the human cortex.In recent years, a growing number of human-specific genetic modifiers have been identified—such as human-specific gene duplications 6, 7—that can induce human-specific traits of brain development. The first experimental test of this idea came from studies of the human-specific gene duplication affecting the ancestral gene Slit-Robo GTPase activating protein 2A (SRGAP2A). Duplication of SRGAP2Aspecifically in the human lineage led to the emergence of the human-specific paralogue SRGAP2C 3, 4. When expressed in mouse cortical PNs in vivo, SRGAP2C inhibits the functions of ancestral SRGAP2A, a postsynaptic protein that regulates excitatory and inhibitory synapse maturation and density in cortical PNs. Because of the truncation of the last 49 amino acids of its F-BAR domain, SRGAP2C is intrinsically unstable but is still able to dimerize with the F-BAR domain of SRGAP2A and thereby reduce SRGAP2A levels through proteasome-dependent degradation 5, 8. The expression of human-specific SRGAP2C in mouse layer 2/3 PNs induces changes in synaptic development that phenocopy a partial loss of function of SRGAP2A and mimic synaptic features characterizing human cortical PNs. These include similar increases in the density of both excitatory and inhibitory synapses received by layer 2/3 PNs and neotenic features of excitatory and inhibitory synaptic development 3–5. These findings indicate that mouse cortical PNs expressing SRGAP2C receive an increased number of synaptic inputs, similar to what is observed in human PNs 9, 10. SRGAP2C may therefore act as a human-specific modifier of cortical connectivity in the human brain.