Selective Depletion of Molecularly Defined Cortical Interneurons in Human Holoprosencephaly with Severe Striatal Hypoplasia
Selective Depletion of Molecularly Defined Cortical Interneurons in Human Holoprosencephaly with Severe Striatal Hypoplasia
复制标题
DOI：
10.1093/cercor/bhp009
复制
发表时间：
2009-09-01
期刊：
影响因子：
3.7
通讯作者：
Sestan, Nenad
中科院分区：
文献类型：
--
作者：
Fertuzinhos, Sofia;Krsnik, Zeljka;Sestan, Nenad
皮质兴奋性GABA能投射神经元和抑制性GABA能中间神经元遵循实质上不同的发育程序。在啮齿类动物中，投射神经元起源于背侧前脑内的祖细胞，而中间神经元则起源于腹侧前脑中的祖细胞。相比之下，有人提出，在人类中，大多数皮质中间神经元来自背侧前脑内的祖细胞，这表明它们的起源和迁移是复杂的，并且在进化上是不同的。然而，分子定义的人类皮质中间神经元亚型是否起源于不同的祖细胞，包括腹侧前脑中的祖细胞，仍然未知。此外，皮质中间神经元的异常与人类疾病有关，但尚未报道明显的细胞群体选择性丧失。在这里，我们表明，皮质中间神经元表达一氧化氮合酶1，神经肽Y，和生长抑素，要么缺席或大幅减少，在胎儿和婴儿的情况下，人类前脑无裂畸形（HPE）与严重的腹侧前脑发育不全。值得注意的是，另一个中间神经元亚型通常丰富的早期胎儿期，标志着钙视网膜蛋白的表达，和不同亚型的投射神经元存在于对照和HPE大脑皮层。这些发现对理解HPE相关临床表现的神经元发病机制和人类皮层中间神经元多样性的发育起源具有重要意义。
Cortical excitatory glutamatergic projection neurons and inhibitory GABAergic interneurons follow substantially different developmental programs. In rodents, projection neurons originate from progenitors within the dorsal forebrain, whereas interneurons arise from progenitors in the ventral forebrain. In contrast, it has been proposed that in humans, the majority of cortical interneurons arise from progenitors within the dorsal forebrain, suggesting that their origin and migration is complex and evolutionarily divergent. However, whether molecularly defined human cortical interneuron subtypes originate from distinct progenitors, including those in the ventral forebrain, remains unknown. Furthermore, abnormalities in cortical interneurons have been linked to human disorders, yet no distinct cell population selective loss has been reported. Here we show that cortical interneurons expressing nitric oxide synthase 1, neuropeptide Y, and somatostatin, are either absent or substantially reduced in fetal and infant cases of human holoprosencephaly (HPE) with severe ventral forebrain hypoplasia. Notably, another interneuron subtype normally abundant from the early fetal period, marked by calretinin expression, and different subtypes of projection neuron were present in the cortex of control and HPE brains. These findings have important implications for the understanding of neuronal pathogenesis underlying the clinical manifestations associated with HPE and the developmental origins of human cortical interneuron diversity.