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 retardation. Here, we sought to understand the mechanisms underlying cognitive deficits under HH exposure. Our results showed that hypobaric hypoxia exposure impaired cognitive function and suppressed dendritic spine density accompanied with increased neck length in both basal and apical hippocampal CA1 region neurons in mice. The expression of PSD95, a vital synaptic scaffolding molecule, is down-regulated by hypobaric hypoxia exposure and post-transcriptionally regulated by cold-inducible RNA-binding protein (Cirbp) through 3′-UTR region binding. PSD95 expressing alleviates hypoxia-induced dendritic spine morphology changes of hippocampal neurons and memory deterioration. Moreover, overexpressed Cirbp in hippocampus rescues HH-induced abnormal expression of PSD95 and attenuates hypoxia-induced dendritic spine injury and cognitive retardation. Thus, our findings reveal a novel mechanism that Cirbp-PSD-95 axis appears to play an essential role in HH-induced cognitive dysfunction in mice.

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. Locations of the CA1 region in hippocampus and distributions of basal and apical spines in pyramidal neurons were shown in Figure 4A .…”

“…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. The animals were sacrificed for further analysis after 1 week of behavioral testing.…”

“…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.…”

“…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…”

CX3CL1/CX3CR1 signal mediates M1-type microglia and accelerates high-altitude-induced forgetting

“…Previous studies have reported that both acute and chronic HH cause cognitive impairment with complex mechanisms, including impaired brain self-regulation, glial vascular defects, oxidative stress, and neuroinflammation, which eventually translate into cognitive deficits ( Wang M. et al, 2022 ). Zhou et al (2021) subjected 8-week-old C57BL/6 mice to simulated 6000 m altitude exposure for 14 days and observed cognitive function impairment, PSD95 downregulation, and dendritic density decline. Xu et al (2014) demonstrated the notable impairment of cognitive function in rats subjected to simulated altitude exposure of 3600 m. Experimental data from Ji et al (2021b) indicated that after 4 and 8 weeks of 4300 m altitude exposure, the hippocampus and cortical neurons of rats showed swelling of neuronal mitochondria and an increase in neuronal apoptosis.…”