Ca²⁺-dependent phosphodiesterase 1 regulates the plasticity of striatal spiny projection neuron glutamatergic synapses.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2024-08-27 Epub Date: 2024-07-25 DOI:10.1016/j.celrep.2024.114540

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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Abstract

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 Ca_V1.3 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.

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Ca2+依赖性磷酸二酯酶1调节纹状体棘突投射神经元谷氨酸能突触的可塑性

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。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.

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