Department of Neuroscience and Physiology, State University of New York Upstate Medical University, 505 Irving Ave., Syracuse, NY 13210, USA.
Int J Mol Sci. 2023 Aug 19;24(16):12965. doi: 10.3390/ijms241612965.
The apical dendrite of a cortical projection neuron (CPN) is generated from the leading process of the migrating neuron as the neuron completes migration. This transformation occurs in the cortical marginal zone (MZ), a layer that contains the Cajal-Retzius neurons and their axonal projections. Cajal-Retzius neurons (CRNs) are well known for their critical role in secreting Reelin, a glycoprotein that controls dendritogenesis and cell positioning in many regions of the developing brain. In this study, we examine the possibility that CRNs in the MZ may provide additional signals to arriving CPNs, that may promote the maturation of CPNs and thus shape the development of the cortex. We use whole embryonic hemisphere explants and multiphoton microscopy to confirm that CRNs display intracellular calcium transients of <1-min duration and high amplitude during early corticogenesis. In contrast, developing CPNs do not show high-amplitude calcium transients, but instead show a steady increase in intracellular calcium that begins at the time of dendritic initiation, when the leading process of the migrating CPN is encountering the MZ. The possible existence of CRN to CPN communication was revealed by the application of veratridine, a sodium channel activator, which has been shown to preferentially stimulate more mature cells in the MZ at an early developmental time. Surprisingly, veratridine application also triggers large calcium transients in CPNs, which can be partially blocked by a cocktail of antagonists that block glutamate and glycine receptor activation. These findings outline a model in which CRN spontaneous activity triggers the release of glutamate and glycine, neurotransmitters that can trigger intracellular calcium elevations in CPNs. These elevations begin as CPNs initiate dendritogenesis and continue as waves in the post-migratory cells. Moreover, we show that the pharmacological blockade of glutamatergic signaling disrupts migration, while forced expression of a bacterial voltage-gated calcium channel (CavMr) in the migrating neurons promotes dendritic growth and migration arrest. The identification of CRN to CPN signaling during early development provides insight into the observation that many autism-linked genes encode synaptic proteins that, paradoxically, are expressed in the developing cortex well before the appearance of synapses and the establishment of functional circuits.
皮质投射神经元（CPN）的顶树突是由迁移神经元的主导过程产生的，当神经元完成迁移时。这种转变发生在皮质边缘区（MZ），MZ 层含有 Cajal-Retzius 神经元及其轴突投射。Cajal-Retzius 神经元（CRN）以其在分泌 Reelin 中的关键作用而闻名，Reelin 是一种糖蛋白，可控制发育中大脑许多区域的树突发生和细胞定位。在这项研究中，我们研究了 MZ 中的 CRN 是否可能向到达的 CPN 提供额外的信号，从而促进 CPN 的成熟，从而塑造皮质的发育。我们使用整个胚胎半球外植体和多光子显微镜证实，CRN 在皮质早期发生过程中显示出持续时间<1 分钟且幅度高的细胞内钙瞬变。相比之下，发育中的 CPN 不会显示高幅度的钙瞬变，而是显示出细胞内钙的稳定增加，当迁移的 CPN 的主导过程遇到 MZ 时，这种增加开始于树突起始时。CRN 到 CPN 通信的可能性是通过维拉帕米（一种钠通道激活剂）的应用揭示的，维拉帕米已被证明在早期发育时间优先刺激 MZ 中更成熟的细胞。令人惊讶的是，维拉帕米的应用也会引发 CPN 中的大钙瞬变，该钙瞬变可以部分被阻断谷氨酸和甘氨酸受体激活的拮抗剂混合物阻断。这些发现概述了一个模型，其中 CRN 自发活动触发谷氨酸和甘氨酸的释放，这些神经递质可以触发 CPN 中的细胞内钙升高。这些升高始于 CPN 开始树突发生，并在迁移后细胞中继续作为波。此外，我们表明，谷氨酸能信号转导的药理学阻断会破坏迁移，而在迁移神经元中强制表达细菌电压门控钙通道（CavMr）会促进树突生长和迁移停滞。在早期发育过程中鉴定出 CRN 到 CPN 的信号传递，为观察到许多自闭症相关基因编码突触蛋白提供了深入了解，这些蛋白矛盾的是，在突触出现和功能回路建立之前，就在发育中的皮质中表达。
