Lack of the peroxiredoxin 6 gene causes impaired spatial memory and abnormal synaptic plasticity

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 Abstract

Behavioral and Synaptic Phenotypes of Female Prdx6−/− Mice

“…The procedure for the MWM test was conducted according to that used in our previous publication [ 8 ]. A circular pool (diameter 110 cm) was filled with water at room temperature (21 °C ± 1 °C).…”

“…Then the hippocampal slices were transferred to a recording chamber for extracellular LTP recording. The recording procedure was conducted as described in our previous publication [ 8 ] . Slices were perfused with ACSF at a speed of 20 rpm.…”

“…PRDX6 is distributed throughout the body, including several brain subregions [ 7 ]. Our recent studies reveal that male Prdx6 −/− mice demonstrate spatial memory deficit and increased stress susceptibility [ 8 , 9 ]. Its functions and distribution in the brain suggest that PRDX6 could be a key molecule in regulating stress-coping mechanisms and cognitive functions.…”

“…Recently, we confirmed that PRDX6 is expressed throughout the brain, including the hippocampus, amygdala, and medial prefrontal cortex [ 16 ]. In addition, it appears to regulate emotional response and spatial memory formation in male mice [ 8 ]. Therefore, whether the Prdx6 gene influences stress-coping mechanisms [ 17 , 18 ] and memory performance [ 19 ] in females is intriguing.…”

Peroxiredoxin 6 Knockout Mice Demonstrate Anxiety Behavior and Attenuated Contextual Fear Memory after Receiving Acute Immobilization Stress

“…PRDX6 is involved in various forms of stress-related disorders [ 21 , 27 , 28 ]. Our previous studies have identified the PRDX6 function in modulating hippocampal synaptic plasticity and memory formation [ 29 , 30 ]. Thus, it is worth investigating whether PRDX6 is involved in stress-related anxiety response and memory performance.…”