SynGAP isoforms differentially regulate synaptic plasticity and dendritic development
SynGAP isoforms differentially regulate synaptic plasticity and dendritic development
复制标题
DOI：
10.7554/elife.56273
复制
发表时间：
2020-06-24
期刊：
影响因子：
7.7
通讯作者：
Huganir, Richard L.
中科院分区：
文献类型：
--
作者：
Araki, Yoichi;Hong, Ingie;Huganir, Richard L.
SynGAP 是一种突触 Ras GTP 酶激活蛋白 (GAP)，具有四种 C 端剪接变体：α 1、α 2、β 和 γ。尽管研究表明 SYNGAP1 与多种认知障碍有关，但尚不清楚哪种 SynGAP 同工型会导致疾病。在这里，我们证明 SynGAP 亚型表现出独特的时空表达模式，并在小鼠神经元的神经元和突触发育中发挥独特的作用。 SynGAP-alpha 1 与 PSD-95 进行液-液相分离，在突触中高度富集，是 LTP 所必需的。相比之下，SynGAP-beta 不结合 PSD-95 PDZ 结构域，突触靶向性较低，并促进树突分枝。 SynGAP-alpha 1 中的突变会破坏相分离和突触靶向，从而消除了其调节可塑性的能力，而是使其像 SynGAP-beta 一样驱动树突发育。这些结果表明，SynGAP 同工型不同的内在生化特性决定了它们的功能，并且各个同工型可能对 SYNGAP1 相关认知障碍的发病机制有不同的贡献。
SynGAP is a synaptic Ras GTPase-activating protein (GAP) with four C-terminal splice variants: alpha 1, alpha 2, beta, and gamma. Although studies have implicated SYNGAP1 in several cognitive disorders, it is not clear which SynGAP isoforms contribute to disease. Here, we demonstrate that SynGAP isoforms exhibit unique spatiotemporal expression patterns and play distinct roles in neuronal and synaptic development in mouse neurons. SynGAP-alpha 1, which undergoes liquid-liquid phase separation with PSD-95, is highly enriched in synapses and is required for LTP. In contrast, SynGAP-beta, which does not bind PSD-95 PDZ domains, is less synaptically targeted and promotes dendritic arborization. A mutation in SynGAP-alpha 1 that disrupts phase separation and synaptic targeting abolishes its ability to regulate plasticity and instead causes it to drive dendritic development like SynGAP-beta. These results demonstrate that distinct intrinsic biochemical properties of SynGAP isoforms determine their function, and individual isoforms may differentially contribute to the pathogenesis of SYNGAP1-related cognitive disorders.