Yamagata Tetsushi, Ogiwara Ikuo, Mazaki Emi, Yanagawa Yuchio, Yamakawa Kazuhiro
Laboratory for Neurogenetics, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
Laboratory for Neurogenetics, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan; Department of Physiology, Nippon Medical School, Tokyo 113-8602, Japan.
Biochem Biophys Res Commun. 2017 Sep 30;491(4):1070-1076. doi: 10.1016/j.bbrc.2017.08.013. Epub 2017 Aug 4.
Nav1.1 and Nav1.2 are the voltage-gated sodium channel pore-forming alpha I and II subunits, encoded by the genes SCN1A and SCN2A. Although mutations of both genes have similarly been described in patients with epilepsy, autism and/or intellectual disability, their expression sites in brain are largely distinct. Nav1.1 was shown to be expressed dominantly in parvalbumin (PV)-positive or somatostatin (SST)-positive inhibitory neurons and in a sparsely-distributed subpopulation of excitatory neurons. In contrast, Nav1.2 has been reported to be dominantly expressed in excitatory neurons. Here we show that Nav1.2 is also expressed in caudal ganglionic eminence (CGE)-derived inhibitory neurons, and expressions of Nav1.1 and Nav1.2 are mutually-exclusive in many of brain regions including neocortex, hippocampus, cerebellum, striatum and globus pallidus. In neocortex at postnatal day 15, in addition to the expression in excitatory neurons we show that Nav1.2 is expressed in reelin (RLN)-positive/SST-negative inhibitory neurons that are presumably single-bouquet cells because of their cortical layer I-limited distribution, and vasoactive intestinal peptide (VIP)-positive neurons that would be multipolar cell because of their layer I/II margin and layer VI distribution. Although Nav1.2 has previously been reported to be expressed in SST-positive cells, we here show that Nav1.2 is not expressed in either of PV-positive or SST-positive inhibitory neurons. PV-positive and SST-positive inhibitory neurons derive from medial ganglionic eminence (MGE) and innervate excitatory neurons, while VIP-positive and RLN-positive/SST-negative inhibitory neurons derive from CGE, innervate on inhibitory neurons and play disinhibitory roles in the neural network. Our results therefore indicate that, while Nav1.1 is expressed in MEG-derived inhibitory neurons, Nav1.2 is expressed in CGE-derived disinhibitory interneurons in addition to excitatory neurons. These findings should contribute to understanding of the pathology of neurodevelopmental diseases caused by SCN2A mutations.
Nav1.1和Nav1.2是电压门控钠通道的孔形成α I和II亚基，分别由基因SCN1A和SCN2A编码。尽管在癫痫、自闭症和/或智力残疾患者中均有这两个基因的突变报道，但它们在大脑中的表达位点有很大差异。研究表明，Nav1.1主要在小白蛋白（PV）阳性或生长抑素（SST）阳性的抑制性神经元以及稀疏分布的兴奋性神经元亚群中表达。相比之下，据报道Nav1.2主要在兴奋性神经元中表达。在此，我们发现Nav1.2也在尾侧神经节隆起（CGE）衍生的抑制性神经元中表达，并且在包括新皮层、海马体、小脑、纹状体和苍白球在内的许多脑区中，Nav1.1和Nav1.2的表达相互排斥。在出生后第15天的新皮层中，除了在兴奋性神经元中表达外，我们还发现Nav1.2在reelin（RLN）阳性/SST阴性的抑制性神经元中表达，这些神经元可能是单束细胞，因为它们局限于皮层I层分布，同时也在血管活性肠肽（VIP）阳性神经元中表达，这些神经元由于其在I/II层边缘和VI层的分布而可能是多极细胞。尽管先前有报道称Nav1.2在SST阳性细胞中表达，但我们在此表明Nav1.2在PV阳性或SST阳性的抑制性神经元中均不表达。PV阳性和SST阳性的抑制性神经元起源于内侧神经节隆起（MGE）并支配兴奋性神经元，而VIP阳性和RLN阳性/SST阴性的抑制性神经元起源于CGE，支配抑制性神经元并在神经网络中发挥去抑制作用。因此，我们的结果表明，虽然Nav1.1在MGE衍生的抑制性神经元中表达，但Nav1.2除了在兴奋性神经元中表达外，还在CGE衍生的去抑制性中间神经元中表达。这些发现应有助于理解由SCN2A突变引起的神经发育疾病的病理学。
