Cirbp-PSD95 Axis Protects Against Hypobaric Hypoxia-Induced Aberrant Morphology of Hippocampal Dendritic Spines and Cognitive Deficits

Abstract

Hypobaric hypoxia (HH) is a typical characteristic of high altitude environment and causes a spectrum of pathophysiological effects, including headaches, gliovascular dysfunction and cognitive slowing. Here, we sought to understand the mechanisms underlying cognitive deficits under HH exposure. Our results showed that HH exposure impaired cognitive function and suppressed dendritic spine density accompanied with increased neck length in both basal and apical hippocampal CA1 region neurons. The expression of PSD95, a critical synaptic scaffolding molecule, is down-regulated by hypoxia exposure and post-transcriptionally controlled by cold-inducible RNA-binding protein (Cirbp) through 3’-UTR region binding. PSD95 expressing alleviates hypoxia-induced neuron dendritic spine plasticity abnormality and memory impairment. Moreover, overexpressed Cirbp in hippocampus rescues hypoxia-induced loss of PSD95 and attenuates hypoxia-induced dendritic spine injury and cognitive outcomes. Thus, our findings reveal a novel mechanism where Cirbp-PSD-95 axis appears to play a key role in hypoxia-induced cognitive abilities impairment in brain.

Resetting Proteostasis of CIRBP with ISRIB Suppresses Neural Stem Cell Apoptosis under Hypoxic Exposure

“…In particular, oxygen consumption by the brain alone accounts for 20% of the total body weight, which accounts for only 2% of the total body mass, and thus, brains are particularly sensitive to oxygen supply [7]. It has been shown that extreme hypoxic exposure can cause fatal diseases such as brain edema, impaired higher brain function such as learning and memory, and increased apoptosis of neurons and altered neuron plasticity [8,9]. Chronic hypoxic exposure results in impairment of speech and visual working memory, executive control function, and psychomotor function.…”

“…Since its discovery as a neuronal rhythm-regulating molecule, the RNA-binding protein CIRBP has received considerable attention [16] and was recently revealed to be involved in regulating neuronal and tumor cell survival and proliferation under hypoxic exposure in multiple signaling pathways [8,9,17,18]. It is thus a hot point in the research field of hypoxia.…”

Dehydroepiandrosterone alleviates hypoxia‐induced learning and memory dysfunction by maintaining synaptic homeostasis

“…As the structural basis of memory and learning functions, dendritic plasticity has been proved to play a vital role in hypoxia‐induced cognitive deficits 21 . First, Golgi Staining was used to identify the dendritic plasticity.…”

“…In the current study, DHEA was dissolved in corn oil and intraperitoneally injected following a dose of 25 and 50 mg/kg every 48 h. After the acclimation period, we randomized the mice into 4 groups ( n = 6 in each group): Con (control), Hyp (hypoxia), Hyp + 25 mg/kg (hypoxia + 25 mg/kg DHEA), and Hyp + 50 mg/kg (hypoxia + 50 mg/kg DHEA). The control group was kept under the normal condition as described above, whereas the other three groups were exposed to a hypoxic condition equal to an altitude of 6000 m by raising in a hypoxia cubage (Fenglei Co. Ltd.) for 14 days continuously according to our former report 21 . Mice were treated with continuous DHEA injection for 2 weeks simultaneous with exposure to hypoxia.…”

“…HT22 cells and primary hippocampal neurons were divided into four groups: Con (control), Hyp (hypoxia), Con + 20 μM DHEA (control + 20 μM DHEA), and Hyp + 20 M DHEA (hypoxia + 20 μM DHEA). A microaerophilic incubation system (Don Whitley) filled with 1% oxygen and 5% carbon dioxide was used to build up hypoxic exposure models in vitro as described previously 21 . The culture medium was pretreated in the microaerophilic incubation system for 9 h before use.…”