Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Germany.
Department of Neurosurgery, Stanford University, USA.
Cereb Cortex. 2018 Dec 1;28(12):4454-4471. doi: 10.1093/cercor/bhy258.
Neural stem cells (NSCs) in the adult mouse hippocampus occur in a specific neurogenic niche, where a multitude of extracellular signaling molecules converges to regulate NSC proliferation as well as fate and functional integration. However, the underlying mechanisms how NSCs react to extrinsic signals and convert them to intracellular responses still remains elusive. NSCs contain a functional endocannabinoid system, including the cannabinoid type-1 receptor (CB1). To decipher whether CB1 regulates adult neurogenesis directly or indirectly in vivo, we performed NSC-specific conditional inactivation of CB1 by using triple-transgenic mice. Here, we show that lack of CB1 in NSCs is sufficient to decrease proliferation of the stem cell pool, which consequently leads to a reduction in the number of newborn neurons. Furthermore, neuronal differentiation was compromised at the level of dendritic maturation pointing towards a postsynaptic role of CB1 in vivo. Deteriorated neurogenesis in NSC-specific CB1 knock-outs additionally resulted in reduced long-term potentiation in the hippocampal formation. The observed cellular and physiological alterations led to decreased short-term spatial memory and increased depression-like behavior. These results demonstrate that CB1 expressed in NSCs and their progeny controls neurogenesis in adult mice to regulate the NSC stem cell pool, dendritic morphology, activity-dependent plasticity, and behavior.
成年小鼠海马中的神经干细胞 (NSC) 存在于特定的神经发生龛位中，其中多种细胞外信号分子汇聚在一起，调节 NSC 的增殖以及命运和功能整合。然而，NSC 如何对外界信号做出反应并将其转化为细胞内反应的潜在机制仍不清楚。NSC 含有功能性内源性大麻素系统，包括大麻素 1 型受体 (CB1)。为了解释 CB1 是否直接或间接地在体内调节成年神经发生，我们使用三转基因小鼠对 NSC 特异性条件性 CB1 失活进行了研究。在这里，我们表明 NSC 中 CB1 的缺失足以减少干细胞池的增殖，从而导致新生神经元数量减少。此外，神经元分化在树突成熟水平受到损害，表明 CB1 在体内具有突触后作用。NSC 特异性 CB1 敲除小鼠中神经发生的恶化还导致海马区长时程增强作用减少。观察到的细胞和生理改变导致短期空间记忆减少和抑郁样行为增加。这些结果表明，NSC 及其祖细胞中表达的 CB1 控制成年小鼠中的神经发生，以调节 NSC 干细胞池、树突形态、活动依赖性可塑性和行为。
