Research Paper Volume 13, Issue 16 pp 20748—20761
Enriched environment remedies cognitive dysfunctions and synaptic plasticity through NMDAR-Ca2+-Activin A circuit in chronic cerebral hypoperfusion rats
- 1 Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China
Received: April 2, 2021 Accepted: August 11, 2021 Published: August 30, 2021
https://doi.org/10.18632/aging.203462How to Cite
Copyright: © 2021 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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 Ca2+ 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 Ca2+ 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-Ca2+-ActA signal pathway has a loop-acting mode, and the environmental enrichment could improve chronic cerebral ischemia cognitive impairment via NMDAR-Ca2+-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-Ca2+-ActA-Wnt/β-catenin signaling loop, providing a therapeutic method for the treatment of CCH.
Abbreviations
CCI: chronic cerebral ischemia; VCI: vascular cognitive impairment; NMDAR: N-methyl-D-aspartic acid receptor; AID: activity-regulated inhibitor of death; ActA: Activin A; CCH: chronic cerebral hypoperfusion; EE: enriched environment; LTP: long-term potentiation; SPF: specific pathogen-free; SD: Sprague Dawley; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; NR2A: NMDAR2A; NR2B: NMDAR2B; DKK-1: DicKKopf-1; SYN: Synapsin; PSD-95: postsynaptic density 95; MAP-2: microtubule Associated protein 2; TGF-β: transforming growth factor-β; BFGF: basic fibroblast growth factor; GAD67: glutamic decarboxylase; PV: parvalbumin.