Shenyu Zhai, Shintaro Otsuka, Jian Xu, Vernon R J Clarke, Tatiana Tkatch, David Wokosin, Zhong Xie, Asami Tanimura, Hitesh K Agarwal, Graham C R Ellis-Davies, Anis Contractor, D James Surmeier
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引用次数: 0
摘要
纹状体棘突投射神经元(SPN)上谷氨酸能突触的长期突触可塑性是学习目标定向行为和习惯的核心。我们的研究发现,SPNs 表现出一种异突触的、一氧化氮(NO)依赖的谷氨酸能 SPN 突触长期突触后抑制(NO-LTD)形式,这种形式优先在静态突触中发挥作用。可塑性由通过 CaV1.3 Ca2+ 通道进入的 Ca2+ 和磷酸二酯酶 1(PDE1)激活所触发,后者会削弱细胞内环磷酸鸟苷(cGMP)和 NO 信号传导。实验和模拟研究都表明,这种对 PDE1 活性的 Ca2+ 依赖性调节可对树突 cGMP 信号进行局部调节。在帕金森病(PD)小鼠模型中,由于神经元间 NO 释放受损,导致 NO-LTD 缺失;重新平衡神经节内神经调节信号恢复了 NO 释放和 NO-LTD。总之,这些研究提供了关于SPN中NO-LTD机制及其在帕金森病等精神运动障碍中作用的重要见解。
Ca2+-dependent phosphodiesterase 1 regulates the plasticity of striatal spiny projection neuron glutamatergic synapses.
Long-term synaptic plasticity at glutamatergic synapses on striatal spiny projection neurons (SPNs) is central to learning goal-directed behaviors and habits. Our studies reveal that SPNs manifest a heterosynaptic, nitric oxide (NO)-dependent form of long-term postsynaptic depression of glutamatergic SPN synapses (NO-LTD) that is preferentially engaged at quiescent synapses. Plasticity is gated by Ca2+ entry through CaV1.3 Ca2+ channels and phosphodiesterase 1 (PDE1) activation, which blunts intracellular cyclic guanosine monophosphate (cGMP) and NO signaling. Both experimental and simulation studies suggest that this Ca2+-dependent regulation of PDE1 activity allows for local regulation of dendritic cGMP signaling. In a mouse model of Parkinson disease (PD), NO-LTD is absent because of impaired interneuronal NO release; re-balancing intrastriatal neuromodulatory signaling restores NO release and NO-LTD. Taken together, these studies provide important insights into the mechanisms governing NO-LTD in SPNs and its role in psychomotor disorders such as PD.
期刊介绍:
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