Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging
Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging
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DOI：
10.1073/pnas.1016442108
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发表时间：
2011-07-05
影响因子：
11.1
通讯作者：
Bilkei-Gorzo, Andras
中科院分区：
文献类型：
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作者：
Albayram, Onder;Alferink, Judith;Bilkei-Gorzo, Andras
大脑老化与认知能力下降有关，认知能力下降伴随着进行性神经炎症变化。内源性大麻素系统（ECS）参与神经胶质细胞活性的调节，并影响与年龄相关的学习和记忆障碍的进展。缺乏编码大麻素受体1（CB 1）的Cnr 1基因（Cnr 1（-/-））的小鼠在空间学习中表现出加速的年龄依赖性缺陷，伴随着海马中主要神经元的丧失。Cnr 1（-/-）小鼠神经元数量的年龄依赖性减少与神经发生减少或癫痫发作无关。然而，在Cnr 1（-/-）小鼠的海马中存在以星形胶质细胞和活化的小胶质细胞的密度增加以及炎症细胞因子IL-6的表达增强为特征的增强的神经炎症。锥体细胞变性和神经炎症的持续过程可以相互加剧，并且都有助于认知缺陷。从前脑GABA能神经元中删除CB 1受体，而不是从海马能神经元中删除CB 1受体，导致海马中类似的神经元丢失和神经炎症增加，如在所有细胞中缺乏CB 1受体的动物中所观察到的。我们的研究结果表明，海马GABA能神经元上的CB 1受体活性通过减少锥体细胞变性和神经炎症来防止年龄依赖性认知衰退。
Brain aging is associated with cognitive decline that is accompanied by progressive neuroinflammatory changes. The endocannabinoid system (ECS) is involved in the regulation of glial activity and influences the progression of age-related learning and memory deficits. Mice lacking the Cnr1 gene (Cnr1(-/-)), which encodes the cannabinoid receptor 1 (CB1), showed an accelerated age-dependent deficit in spatial learning accompanied by a loss of principal neurons in the hippocampus. The age-dependent decrease in neuronal numbers in Cnr1(-/-) mice was not related to decreased neurogenesis or to epileptic seizures. However, enhanced neuroinflammation characterized by an increased density of astrocytes and activated microglia as well as an enhanced expression of the inflammatory cytokine IL-6 during aging was present in the hippocampus of Cnr1(-/-) mice. The ongoing process of pyramidal cell degeneration and neuroinflammation can exacerbate each other and both contribute to the cognitive deficits. Deletion of CB1 receptors from the forebrain GABAergic, but not from the glutamatergic neurons, led to a similar neuronal loss and increased neuroinflammation in the hippocampus as observed in animals lacking CB1 receptors in all cells. Our results suggest that CB1 receptor activity on hippocampal GABAergic neurons protects against age-dependent cognitive decline by reducing pyramidal cell degeneration and neuroinflammation.