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丰富环境通过慢性脑低灌注大鼠 NMDA 受体-Ca-激活素 A 回路纠正认知功能障碍和突触可塑性。

Enriched environment remedies cognitive dysfunctions and synaptic plasticity through NMDAR-Ca-Activin A circuit in chronic cerebral hypoperfusion rats.

机构信息

Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China.

出版信息

Aging (Albany NY). 2021 Aug 30;13(16):20748-20761. doi: 10.18632/aging.203462.

DOI:10.18632/aging.203462
PMID:34462377
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8436900/
Abstract

Chronic cerebral ischemia (CCI) is one of the critical factors in the occurrence and development of vascular cognitive impairment (VCI). Apoptosis of nerve cells and changes in synaptic activity after CCI are the key factors to induce VCI. Synaptic stimulation up-regulates intraneuronal Ca level through N-methyl-D-aspartic acid receptor (NMDAR) via induction of the activity-regulated inhibitor of death (AID) expression to produce active-dependent neuroprotection. Moreover, the regulation of synaptic plasticity could improve cognition and learning ability. Activin A (ActA), an exocrine protein of AID, can promote NMDAR phosphorylation and participate in the regulation of synaptic plasticity. We previously found that exogenous ActA can improve the cognitive function of rats with chronic cerebral ischemia and enhance the oxygenated glucose deprivation of intracellular Ca level. In addition to NMDAR, the Wnt pathway is critical in the positive regulation of LTP through activation or inhibition. It plays an essential role in synaptic transmission and activity-dependent synaptic plasticity. The enriched environment can increase ActA expression during CCI injury. We speculated that the NMDAR-Ca-ActA signal pathway has a loop-acting mode, and the environmental enrichment could improve chronic cerebral ischemia cognitive impairment via NMDAR-Ca-ActA, Wnt/β-catenin pathway is involved in this process. For the hypothesis verification, this study intends to establish chronic cerebral hypoperfusion (CCH) rat model, explore the improvement effect of enriched environment on VCI, detect the changes in plasticity of synaptic morphology and investigate the regulatory mechanism NMDAR-Ca-ActA-Wnt/β-catenin signaling loop, providing a therapeutic method for the treatment of CCH.

摘要

慢性脑缺血（CCI）是血管性认知障碍（VCI）发生和发展的关键因素之一。CCI 后神经细胞凋亡和突触活动变化是诱导 VCI 的关键因素。突触刺激通过诱导活性调节死亡抑制剂（AID）的表达，通过 N-甲基-D-天冬氨酸受体（NMDAR）上调细胞内 Ca 水平，产生活性依赖性神经保护。此外，突触可塑性的调节可以改善认知和学习能力。激活素 A（ActA）是 AID 的外分泌蛋白，可促进 NMDAR 磷酸化并参与突触可塑性的调节。我们之前发现，外源性 ActA 可以改善慢性脑缺血大鼠的认知功能，并增强细胞内 Ca 水平的氧葡萄糖剥夺。除了 NMDAR 外，Wnt 通路在通过激活或抑制增强 LTP 中对正调节也很重要。它在突触传递和活性依赖性突触可塑性中起重要作用。丰富的环境可以在 CCI 损伤期间增加 ActA 的表达。我们推测 NMDAR-Ca-ActA 信号通路具有循环作用模式，环境丰富可以通过 NMDAR-Ca-ActA 改善慢性脑缺血认知障碍，Wnt/β-连环蛋白通路参与这一过程。为了验证假设，本研究旨在建立慢性脑低灌注（CCH）大鼠模型，探讨丰富环境对 VCI 的改善作用，检测突触形态可塑性的变化，并探讨 NMDAR-Ca-ActA-Wnt/β-catenin 信号环路的调节机制，为 CCH 的治疗提供一种治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/849f/8436900/389f5f0a6a79/aging-13-203462-g006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/849f/8436900/574562cf1471/aging-13-203462-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/849f/8436900/389f5f0a6a79/aging-13-203462-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/849f/8436900/3baa8f23c12a/aging-13-203462-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/849f/8436900/78e3697926d7/aging-13-203462-g002.jpg
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