Abstract
Peroxiredoxin 6 (PRDX6) is expressed dominantly in the astrocytes and exerts either neuroprotective or neurotoxic effects in the brain. Although PRDX6 can modulate several signaling cascades involving cognitive functions, its physiological role in spatial memory has not been investigated yet. This study aims to explore the function of the Prdx6 gene in spatial memory formation and synaptic plasticity. We first tested Prdx6−/− mice on a Morris water maze task and found that their memory performance was defective, along with reduced long-term potentiation (LTP) in CA3-CA1 hippocampal synapses recorded from hippocampal sections of home-caged mice. Surprisingly, after the probe test, these knockout mice exhibited elevated hippocampal LTP, higher phosphorylated ERK1/2 level, and decreased reactive astrocyte markers. We further reduced ERK1/2 phosphorylation by administering MEK inhibitor, U0126, into Prdx6−/− mice before the probe test, which reversed their spatial memory deficit. This study is the first one to report the role of PRDX6 in spatial memory and synaptic plasticity. Our results revealed that PRDX6 is necessary for maintaining spatial memory by modulating ERK1/2 phosphorylation and astrocyte activation.Graphic
Highlights
Spatial memory impairment is one of the most common pathologies in aging processes, early Alzheimer’s disease, and some psychiatric disorders [1,2,3]
Hyperphosphorylation of Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and upregulation of PSD95 and cytosolic phospholipase A2 (cPLA2) were detected in the hippocampus after a probe test in Prdx6−/− mice To better understand the molecular mechanism underlying spatial memory deficit, we investigated expression of various synaptic proteins after the probe test (Fig. 5a), including Brain-derived neurotrophic factor (BDNF), PSD95, phosphorylated ERK1/2, cPLA2, phosphorylated Akt1, and phosphorylated CaMKII
Our results identify the novel role of peroxiredoxin 6 (PRDX6) in spatial memory formation and synaptic plasticity
Summary
Spatial memory impairment is one of the most common pathologies in aging processes, early Alzheimer’s disease, and some psychiatric disorders [1,2,3]. Oxidative damage and inflammation are two major causes of spatial memory impairment in these brain diseases [4]. The level of reactive oxygen species (ROS) is regulated by antioxidants during synaptic plasticity [5]. Either lower or higher levels of ROS than homeostatic level may cause impairment of synaptic plasticity and memory performance. Growing evidence has revealed that various endogenous antioxidant enzymes regulate oxidative defense mechanisms and inflammatory responses [6, 7], their physiological roles in modulating cellular signaling for synaptic plasticity and spatial memory formation are not clear yet. Peroxiredoxins (PRDXs) belong to a conserved 6-member superfamily of peroxidases that exist in many organisms [8]. Among the six members (PRDX 1–6), peroxiredoxin 6 (PRDX6) contains only 1-cysteine (1-cys)
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