Department of Neurobiology and Anatomy, W.M. Keck Center for the Neurobiology of Learning and Memory, McGovern Medical School, The University of Texas Health Center At Houston, 6431 Fannin Street, Suite MSB 7.046, Houston, TX, 77030, USA.
Sci Rep. 2021 Jul 22;11(1):14931. doi: 10.1038/s41598-021-94393-0.
Kinases play critical roles in synaptic and neuronal changes involved in the formation of memory. However, significant gaps exist in the understanding of how interactions among kinase pathways contribute to the mechanistically distinct temporal domains of memory ranging from short-term memory to long-term memory (LTM). Activation of protein kinase A (PKA) and mitogen-activated protein kinase (MAPK)-ribosomal S6 kinase (RSK) pathways are critical for long-term enhancement of neuronal excitability (LTEE) and long-term synaptic facilitation (LTF), essential processes in memory formation. This study provides new insights into how these pathways contribute to the temporal domains of memory, using empirical and computational approaches. Empirical studies of Aplysia sensory neurons identified a positive feedforward loop in which the PKA and ERK pathways converge to regulate RSK, and a negative feedback loop in which p38 MAPK inhibits the activation of ERK and RSK. A computational model incorporated these findings to simulate the dynamics of kinase activity produced by different stimulus protocols and predict the critical roles of kinase interactions in the dynamics of these pathways. These findings may provide insights into the mechanisms underlying aberrant synaptic plasticity observed in genetic disorders such as RASopathies and Coffin-Lowry syndrome.
激酶在参与记忆形成的突触和神经元变化中发挥着关键作用。然而，对于激酶途径之间的相互作用如何有助于从短期记忆到长期记忆（LTM）的记忆的机制上不同的时间域，我们的理解还存在很大的差距。蛋白激酶 A（PKA）和丝裂原活化蛋白激酶（MAPK）-核糖体 S6 激酶（RSK）途径的激活对于神经元兴奋性的长期增强（LTEE）和长时程突触易化（LTF）至关重要，这是记忆形成的基本过程。本研究使用经验和计算方法，为这些途径如何有助于记忆的时间域提供了新的见解。对 Aplysia 感觉神经元的实证研究确定了一个正反馈回路，其中 PKA 和 ERK 途径汇聚以调节 RSK，以及一个负反馈回路，其中 p38 MAPK 抑制 ERK 和 RSK 的激活。一个计算模型结合了这些发现，以模拟不同刺激方案产生的激酶活性的动力学，并预测激酶相互作用在这些途径的动力学中的关键作用。这些发现可能为 RAS 病和 Coffin-Lowry 综合征等遗传疾病中观察到的异常突触可塑性的机制提供了新的见解。
