Endogenous Syngap1 alpha splice forms promote cognitive function and seizure protection.
Endogenous Syngap1 alpha splice forms promote cognitive function and seizure protection.
复制标题
DOI：
10.7554/elife.75707
复制
发表时间：
2022-04-08
期刊：
影响因子：
7.7
通讯作者：
Rumbaugh, Gavin
中科院分区：
文献类型：
--
作者：
Kilinc, Murat;Arora, Vineet;Creson, Thomas K.;Rojas, Camilo;Le, Aliza A.;Lauterborn, Julie;Wilkinson, Brent;Hartel, Nicolas;Graham, Nicholas;Reich, Adrian;Gou, Gemma;Araki, Yoichi;Bayes, Alex;Coba, Marcelo;Lynch, Gary;Miller, Courtney A.;Rumbaugh, Gavin
SYNGAP1的功能丧失变异导致一种由认知障碍、自闭症特征和癫痫定义的发育性脑病。Syngap1剪接导致不同功能蛋白亚型的表达。剪接通过编码不同的C-末端基序赋予SynGAP蛋白多种细胞功能。然而，目前尚不清楚这些不同的剪接序列在体内如何调节神经元的功能和行为。SynGAP-α1/2 C末端剪接变异体在小鼠中的表达减少导致严重的表型，包括存活减少、学习障碍和癫痫潜伏期减少。相反，α1/2表达上调改善了学习能力，延长了癫痫发作潜伏期。表达α1特异性突变的小鼠，在不改变蛋白表达的情况下扰乱SynGAP细胞功能，促进癫痫发作，破坏突触可塑性，并损害学习。这些发现表明，带有α1/2剪接序列的内源性SynGAP亚型可促进认知功能，并给予癫痫保护。调节SynGAP-α的表达或功能可能是广泛改善认知功能和减轻癫痫发作的可行治疗策略。
Loss-of-function variants in SYNGAP1 cause a developmental encephalopathy defined by cognitive impairment, autistic features, and epilepsy. SYNGAP1 splicing leads to expression of distinct functional protein isoforms. Splicing imparts multiple cellular functions of SynGAP proteins through coding of distinct C-terminal motifs. However, it remains unknown how these different splice sequences function in vivo to regulate neuronal function and behavior. Reduced expression of SynGAP-α1/2 C-terminal splice variants in mice caused severe phenotypes, including reduced survival, impaired learning, and reduced seizure latency. In contrast, upregulation of α1/2 expression improved learning and increased seizure latency. Mice expressing α1-specific mutations, which disrupted SynGAP cellular functions without altering protein expression, promoted seizure, disrupted synapse plasticity, and impaired learning. These findings demonstrate that endogenous SynGAP isoforms with α1/2 spliced sequences promote cognitive function and impart seizure protection. Regulation of SynGAP-αexpression or function may be a viable therapeutic strategy to broadly improve cognitive function and mitigate seizure.