LIMK1 Regulates Long-Term Memory and Synaptic Plasticity via the Transcriptional Factor CREB
LIMK1 Regulates Long-Term Memory and Synaptic Plasticity via the Transcriptional Factor CREB
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DOI：
10.1128/mcb.01263-14
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发表时间：
2015-04-01
影响因子：
5.3
通讯作者：
Jia, Zhengping
中科院分区：
文献类型：
--
作者：
Todorovski, Zarko;Asrar, Suhail;Jia, Zhengping
LIMK 1基因的缺失与威廉姆斯综合征有关，威廉姆斯综合征是一种独特的神经发育障碍，其特征是视觉空间认知和长期记忆（LTM）的严重缺陷。然而，LIMK 1是否有助于这些赤字仍然难以捉摸。在这里，我们发现LIMK 1基因敲除（LIMK 1（-/-））小鼠在LTM中严重受损，但短期记忆（STM）没有受损。此外，LIMK 1（-/-）小鼠在晚期长时程增强（L-LTP）中有选择性缺陷，这是一种长期持续的突触可塑性形式，特别是形成LTM所需的。此外，我们表明，LIMK 1相互作用和调节环AMP反应元件结合蛋白（CREB），一个广泛研究的转录因子的LTM的关键活性。重要的是，LIMK 1（-/-）小鼠中的L-LTP和LTM缺陷都可以通过增加CREB的活性来挽救。这些结果提供了强有力的证据，LIMK 1缺失足以导致LTM缺陷，并且这种缺陷可归因于CREB功能减退。我们的研究在小鼠中发现了一种直接的基因-表型联系，并提供了一种通过增强成人大脑中CREB活性来恢复威廉姆斯综合征患者LTM的潜在策略。
Deletion of the LIMK1 gene is associated with Williams syndrome, a unique neurodevelopmental disorder characterized by severe defects in visuospatial cognition and long-term memory (LTM). However, whether LIMK1 contributes to these deficits remains elusive. Here, we show that LIMK1-knockout (LIMK1(-/-)) mice are drastically impaired in LTM but not short-term memory (STM). In addition, LIMK1(-/-) mice are selectively defective in late-phase long-term potentiation (L-LTP), a form of long-lasting synaptic plasticity specifically required for the formation of LTM. Furthermore, we show that LIMK1 interacts and regulates the activity of cyclic AMP response element-binding protein (CREB), an extensively studied transcriptional factor critical for LTM. Importantly, both L-LTP and LTM deficits in LIMK1(-/-) mice are rescued by increasing the activity of CREB. These results provide strong evidence that LIMK1 deletion is sufficient to lead to an LTM deficit and that this deficit is attributable to CREB hypofunction. Our study has identified a direct gene-phenotype link in mice and provides a potential strategy to restore LTM in patients with Williams syndrome through the enhancement of CREB activity in the adult brain.