Department of Physiology, Faculty of Medicine, Saitama Medical University, Moroyama, Saitama 350-0495, Japan.
The Linda and Jack Gill Center for Biomolecular Sciences, Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405.
Proc Natl Acad Sci U S A. 2022 Sep 13;119(37):e2122700119. doi: 10.1073/pnas.2122700119. Epub 2022 Sep 6.
Columnar structure is one of the most fundamental morphological features of the cerebral cortex and is thought to be the basis of information processing in higher animals. Yet, how such a topographically precise structure is formed is largely unknown. Formation of columnar projection of layer 4 (L4) axons is preceded by thalamocortical formation, in which type 1 cannabinoid receptors (CB1R) play an important role in shaping barrel-specific targeted projection by operating spike timing-dependent plasticity during development (Itami , 36, 7039-7054 [2016]; Kimura & Itami, 39, 3784-3791 [2019]). Right after the formation of thalamocortical projections, CB1Rs start to function at L4 axon terminals (Itami & Kimura, 32, 15000-15011 [2012]), which coincides with the timing of columnar shaping of L4 axons. Here, we show that the endocannabinoid 2-arachidonoylglycerol (2-AG) plays a crucial role in columnar shaping. We found that L4 axon projections were less organized until P12 and then became columnar after CB1Rs became functional. By contrast, the columnar organization of L4 axons was collapsed in mice genetically lacking diacylglycerol lipase α, the major enzyme for 2-AG synthesis. Intraperitoneally administered CB1R agonists shortened axon length, whereas knockout of CB1R in L4 neurons impaired columnar projection of their axons. Our results suggest that endocannabinoid signaling is crucial for shaping columnar axonal projection in the cerebral cortex.
柱状结构是大脑皮层最基本的形态特征之一，被认为是高等动物信息处理的基础。然而，这种具有精确拓扑结构的结构是如何形成的，在很大程度上仍是未知的。第 4 层（L4）轴突的柱状投射的形成先于丘脑皮质形成，其中 1 型大麻素受体（CB1R）在发育过程中通过操作尖峰时间依赖性可塑性在形成桶状特异性靶向投射中发挥重要作用（Itami，36，7039-7054 [2016]；Kimura 和 Itami，39，3784-3791 [2019]）。在丘脑皮质投射形成后，CB1R 开始在 L4 轴突末梢发挥作用（Itami 和 Kimura，32，15000-15011 [2012]），这与 L4 轴突柱状形成的时间一致。在这里，我们表明内源性大麻素 2-花生四烯酸甘油（2-AG）在柱状形成中起着关键作用。我们发现，L4 轴突投射直到 P12 才变得更有组织，然后在 CB1R 发挥功能后变得具有柱状结构。相比之下，在基因敲除二酰基甘油脂肪酶 α（2-AG 合成的主要酶）的小鼠中，L4 轴突的柱状结构被破坏。腹腔内给予 CB1R 激动剂缩短了轴突长度，而 L4 神经元中 CB1R 的缺失则损害了其轴突的柱状投射。我们的结果表明，内源性大麻素信号对于大脑皮层中柱状轴突投射的形成至关重要。
