Acute and Chronic Sleep Deprivation-Related Changes in N-methyl-D-aspartate Receptor—Nitric Oxide Signalling in the Rat Cerebral Cortex with Reference to Aging and Brain Lateralization

Abstract

Aging and chronic sleep deprivation (SD) are well-recognized risk factors for Alzheimer’s disease (AD), with N-methyl-D-aspartate receptor (NMDA) and downstream nitric oxide (NO) signalling implicated in the process. Herein, we investigate the impact of the age- and acute or chronic SD-dependent changes on the expression of NMDA receptor subunits (NR1, NR2A, and NR2B) and on the activities of NO synthase (NOS) isoforms in the cortex of Wistar rats, with reference to cerebral lateralization. In young adult controls, somewhat lateralized seasonal variations in neuronal and endothelial NOS have been observed. In aged rats, overall decreases in NR1, NR2A, and NR2B expression and reduction in neuronal and endothelial NOS activities were found. The age-dependent changes in NR1 and NR2B significantly correlated with neuronal NOS in both hemispheres. Changes evoked by chronic SD (dysfunction of endothelial NOS and the increasing role of NR2A) differed from those evoked by acute SD (increase in inducible NOS in the right side). Collectively, these results demonstrate age-dependent regulation of the level of NMDA receptor subunits and downstream NOS isoforms throughout the rat brain, which could be partly mimicked by SD. As described herein, age and SD alterations in the prevalence of NMDA receptors and NOS could contribute towards cognitive decline in the elderly, as well as in the pathobiology of AD and the neurodegenerative process.

Sleep, brain vascular health and ageing

“…It was shown that ageing decreases expression of NMDA receptors and downregulates NOS isoforms in some SD groups. This also corroborates with cognitive decline in the elderly (Kristofikova et al 2019). SD activates oxidoinflammation in the prefrontal cortex, decreasing glutamate receptor subunits and PSD95 in PND33 (postnatal day 33) in rats.…”

An Overview of NO Signaling Pathways in Aging

“…Chronic SD led to eNOS dysfunction and NR2A increased activity, while the acute SD elevated iNOS in the right side of rats' brains. Chronic SD and age both affected the NMDA prevalence and NOS functions in a similar manner in which AD does [246].…”

“…Moreover, SD has been suggested to affect NMDA receptors which are involved in sleepwake cycles [244,245]. Kristofikova et al (2019) found that the expression of subunits of NMDA receptors (NR1, NR2A, and NR2B) and eNOS, as well as nNOS, were reduced in aged rats. Changes to the nNOS were correlated with NR1 and NR2B in both hemispheres of animals.…”

High frequency repetitive transcranial magnetic stimulation alleviates cognitive deficits in 3xTg-AD mice by modulating the PI3K/Akt/GLT-1 axis

“…This study found that rTMS can reverse the reduction of PSD-95 and SYP levels in the hippocampus of 3xTg-AD mice. Autopsy studies also found that the mRNA and protein expression levels of the postsynaptic glutamate receptors NR1, NR2A, and NR2B subunits decreased in AD patients [ 50 ]. In this study, it was found that the expression levels of NR1, NR2A and NR2B subunit proteins were down-regulated in the brain of 3xTg-AD mice, while rTMS only increased the level of NR2B, suggesting that rTMS may regulate glutamatergic transmission mainly by regulating NR2B.…”