University of Montreal, Montreal, Quebec H3T 1J4, Canada.
J Neurosci. 2011 Jan 26;31(4):1489-99. doi: 10.1523/JNEUROSCI.4134-09.2011.
Endocannabinoids (eCBs) are retrograde neurotransmitters that modulate the function of many types of synapses. The presence of eCBs, their CB1 receptor (CB1R), and metabolizing enzymes at embryonic and early postnatal periods have been linked to developmental processes such as neuronal proliferation, differentiation, and migration, axon guidance, and synaptogenesis. Here, we demonstrate the presence of a functional eCB system in the developing visual system and the role of CB1R during axon growth and retinothalamic development. Pharmacological treatment of retinal explants and primary cortical neuron cultures with ACEA, a selective CB1R agonist, induced a collapse of the growth cone (GC). Furthermore the application of AM251, a CB1R inverse agonist, to the neuronal cultures increased the surface area of GC. In vivo, intraocular injection of ACEA diminished retinal projection growth, while AM251 promoted growth and caused aberrant projections. In addition, compared with their wild-type littermates, CB1R-deficient adult mice revealed a lower level of eye-specific segregation of retinal projections in the dorsal lateral geniculate nucleus. Finally, we found that pharmacological modulation of CB1R affected the trafficking of Deleted in colorectal cancer (DCC) receptor to the plasma membrane in a PKA-dependent manner. Moreover, pharmacological inhibition or genetic inactivation of DCC abolished the CB1R-induced reorganization of the GC. Overall, these findings establish a mechanism by which the CB1R influences GC behavior and nervous system development in concerted action with DCC.
内源性大麻素（eCBs）是逆行神经递质，可调节多种类型突触的功能。在胚胎期和出生后早期，eCBs、其 CB1 受体（CB1R）和代谢酶的存在与神经元增殖、分化和迁移、轴突导向和突触发生等发育过程有关。在这里，我们证明了功能性 eCB 系统在发育中的视觉系统中的存在，以及 CB1R 在轴突生长和视丘脑发育过程中的作用。用选择性 CB1R 激动剂 ACEA 处理视网膜外植体和原代皮质神经元培养物会诱导生长锥（GC）崩溃。此外，将 CB1R 反向激动剂 AM251 应用于神经元培养物会增加 GC 的表面积。在体内，向眼内注射 ACEA 会减少视网膜投射的生长，而 AM251 则会促进生长并导致异常投射。此外，与野生型同窝仔相比，CB1R 缺陷型成年小鼠在背外侧膝状体核中表现出较低水平的视网膜投射的眼特异性分离。最后，我们发现 CB1R 的药理学调节以 PKA 依赖的方式影响Deleted in colorectal cancer (DCC) 受体向质膜的运输。此外，DCC 的药理学抑制或遗传失活消除了 CB1R 诱导的 GC 重组。总体而言，这些发现建立了一种机制，通过该机制，CB1R 与 DCC 协同作用影响 GC 行为和神经系统发育。
