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.

Department of Psychiatry and Medical Psychology 3rd Faculty of Medicine of Charles University 11636 Prague Czech Republic

Institute of Computer Science Academy of Sciences of the Czech Republic Pod vodarenskou vezi 2 182 07 Prague 8 Czech Republic

International Centre for Neurotherapeutics Dublin City University 9 Dublin Ireland

National Institute of Mental Health Topolova 748 250 67 Klecany Czech Republic

See more in PubMed

Costandi M. Amyloid awakenings. Nature. 2013;497:19–20. doi: 10.1038/497S19a. PubMed DOI

Huitron-Resendiz S., Sanchez-Alavez M., Gallegos R., Berg G., Crawford E., Giacchino J.L., Games D., Henriksen S.J., Criado J.R. Age-independent and age-related deficits in visuospatial learning, sleep-wake states, thermoregulation and motor activity in PDAPP mice. Brain Res. 2002;928:126–137. doi: 10.1016/S0006-8993(01)03373-X. PubMed DOI

Petrasek T., Vojtechova I., Lobellova V., Popelikova A., Janikova M., Broyka H., Houdek P., Sladek M., Sumova A., Kristofikova Z., et al. The McGill transgenic rat model of Alzheimer’s disease displays cognitive and motor impairments, changes in anxiety and social behavior, and altered circadian activity. Front. Aging Neurosci. 2018;10:250. doi: 10.3389/fnagi.2018.00250. PubMed DOI PMC

Silva R.H., Abilio V.C., Takatsu A.L., Kameda S.R., Grassl C., Chehin A.B., Medrano W.A., Calzavara M.B., Registro S., Andersen M.L., et al. Role of hippocampal oxidative stress in memory deficits induced by sleep deprivation in mice. Neuropharmacology. 2004;46:895–903. doi: 10.1016/j.neuropharm.2003.11.032. PubMed DOI

Butterfield D.A., Drake J., Pocernich C., Castegna A. Evidence of oxidative damage in Alzheimer’s brain: Central role for amyloid beta-peptide. Trends Mol. Med. 2001;7:548–554. doi: 10.1016/S1471-4914(01)02173-6. PubMed DOI

Butterfield D.A., Howard B.J., LaFontaine M.A. Brain oxidative stress in animal models of accelerated aging and the age-related neurodegenerative disorders, Alzheimer’s disease and Huntington’s disease. Curr. Med. Chem. 2001;8:815–858. doi: 10.2174/0929867013373048. PubMed DOI

Kang J.E., Lim M.M., Bateman R.J., Lee J.J., Smyth L.P., Cirrito J.R., Fujiki N., Nishino S., Holtzman D.M. Amyloid-β dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009;326:1005–1007. doi: 10.1126/science.1180962. PubMed DOI PMC

Spira A.P., Gamaldo A.A., An Y., Wu M.N., Simonsick E.M., Bilgel M., Zhou Y., Wong D.F., Ferucci L., Resnick S.M. Self-reported sleep and β-amyloid deposition in community-dwelling older adults. JAMA Neurol. 2013 doi: 10.1001/jamaneurol.2013.4258. PubMed DOI PMC

Shen Y.X., Xu S.Y., Wei W., Wang X.L., Wang H., Sun X. Melatonin blocks rat hippocampal neuronal apoptosis induced by amyloid beta-peptide 25-35. J. Pineal Res. 2002;32:163–167. doi: 10.1034/j.1600-079x.2002.1o839.x. PubMed DOI

Matsubara E., Bryant-Thomas T., Pacheco Quinto J., Henry T.L., Poeggeler B., Herbert D., Crus-Sanchez F., Chyan Y.J., Smith M.A., Perry G., et al. Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer’s disease. J. Neurochem. 2003;85:1101–1108. doi: 10.1046/j.1471-4159.2003.01654.x. PubMed DOI

Lahiri D.K., Cen D., Ge Y.W., Bondy S.C., Sharman E.H. Dietary supplementation with melatonin reduces levels of amyloid beta-peptides in the murine cerebral cortex. J. Pineal Res. 2004;36:224–231. doi: 10.1111/j.1600-079X.2004.00121.x. PubMed DOI

Quin J., Kulhanek D., Nowlin J., Jones R., Practico D., Rokach J., Stackman R. Chronic melatonin therapy fails to alter amyloid burden or oxidative damage in old Tg2576 mice: Implications for clinical trials. Brain Res. 2005;1037:209–213. doi: 10.1016/j.brainres.2005.01.023. PubMed DOI

Masilamoni J.G., Jesudason E.P., Dhandayuthapani S., Ashok B.S., Vignesh S., Jerabaj C.E., Paul S.F.D., Jayakumar R. The neuroprotective role of melatonin against amyloid β peptide injected mice. Free Radic. Res. 2008;42:661–673. doi: 10.1080/10715760802277388. PubMed DOI

Roh J.H., Jiang H., Finn M.B., Stewart F.R., Mahan T.E., Cirrito J.R., Heda A., Snider B.J., Li M., Yanagisawa M., et al. Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer’s disease. J. Exp. Med. 2014;211:2487–2496. doi: 10.1084/jem.20141788. PubMed DOI PMC

Rothman S.M., Herdener N., Frankola K.A., Mughal M.R., Mattson M.P. Chronic mild sleep restriction accentuates contextual memory impairments and accumulations of cortical Aβ and pTau in a mouse model of Alzheimer’s disease. Brain Res. 2013;1529:200–208. doi: 10.1016/j.brainres.2013.07.010. PubMed DOI PMC

Di Meco A., Joshi Y.B., Pratico D. Sleep deprivation impairs memory, tau metabolism, and synaptic integrity of a mouse model of Alzheimer’s disease with plaques and tangles. Neurobiol. Aging. 2014;35:1813–1820. doi: 10.1016/j.neurobiolaging.2014.02.011. PubMed DOI

Liu S.J., Wang J.Z. Alzheimer-like tau phosphorylation induced by wortmannin in vivo and its attenuation by melatonin. Acta Pharmacol. Sin. 2002;23:183–187. PubMed

Zhu L.Q., Wang S.H., Ling Z.Q., Wang D.L., Wang J.Z. Effect of inhibiting melatonin biosynthesis on spatial memory retention and tau phosphorylation in the rat. J. Pineal Res. 2004;37:71–77. doi: 10.1111/j.1600-079X.2004.00136.x. PubMed DOI

Stenberg D. Neuroanatomy and neurochemistry of sleep. Cell. Mol. Life Sci. 2007;64:1187–1204. doi: 10.1007/s00018-007-6530-3. PubMed DOI PMC

Watson C.J., Baghdoyan H.A., Lydic R. Neuropharmacology of sleep and wakefulness. Sleep Med. Clin. 2010;5:513–528. doi: 10.1016/j.jsmc.2010.08.003. PubMed DOI PMC

Cortese B.M., Mitchell T.R., Galloway M.P., Prevost K.E., Fang J., Moore G.J., Uhde T.W. Region-specific alteration in brain glutamate: Possible relationship to risk-taking behavior. Physiol. Behav. 2010;99:445–450. doi: 10.1016/j.physbeh.2009.12.005. PubMed DOI PMC

Dash M.B., Douglas C.L., Vyazovskiy V.V., Cirelli C., Tononi G. Long-term homeostasis of extracellular glutamate in the rat cerebral cortex across sleep and waking states. J. Neurosci. 2009;29:620–629. doi: 10.1523/JNEUROSCI.5486-08.2009. PubMed DOI PMC

Prince T.M., Abel T. The impact of sleep loss on hippocampal function. Learn. Mem. 2013;20:558–569. doi: 10.1101/lm.031674.113. PubMed DOI PMC

Xie M., Yan J., He C., Yang L., Tan G., Li C., Hu Z., Wang J. Short/term sleep deprivation impairs spatial working memory and modulates expression levels of ionotropic glutamate receptor subunits in the hippocampus. Behav. Brain Res. 2015;286:64–70. doi: 10.1016/j.bbr.2015.02.040. PubMed DOI

Xie M., Li C., He C., Yang L., Tan G., Yan J., Wang J., Hu Z. Short-term sleep deprivation disrupts the molecular composition of ionotropic glutamate receptors in the entorhinal cortex and impairs the rat spatial reference memory. Behav. Brain Res. 2016;300:70–76. doi: 10.1016/j.bbr.2015.10.002. PubMed DOI

Cirelli C., Tononi G. Gene expression in the brain across the sleep-waking cycle. Brain Res. 2000;885:303–321. doi: 10.1016/S0006-8993(00)03008-0. PubMed DOI

Magnusson K.R., Nelson S.E., Young A.B. Age-related changes in the protein expression of subunits of the NMDA receptor. Brain Res. Mol. Brain Res. 2002;99:40–45. doi: 10.1016/S0169-328X(01)00344-8. PubMed DOI

Liu P., Smith P.F., Darlington C.L. Glutamate receptor subunits expression in memory-associated brain structures: Regional variations and effects of aging. Synapse. 2008;62:834–841. doi: 10.1002/syn.20563. PubMed DOI

Kristofikova Z., Vrajova M., Sirova J., Vales K., Petrasek T., Schonig K., Tews B., Schwab M., Bartsch D., Stuchlik A., et al. N-methyl-d-aspartate receptor—Nitric oxide synthase pathway in the cortex of NOGO-A-deficient rats in relation to brain laterality and schizophrenia. Front. Behav. Neurosci. 2013;7:90. doi: 10.3389/fnbeh.2013.00090. PubMed DOI PMC

Bi H., Sze C.I. N-methyl-d-aspartate receptor subunit NR2A and NR2B messenger RNA levels are altered in the hippocampus and entorhinal cortex in Alzheimer’s disease. J. Neurol. Sci. 2002;200:11–18. doi: 10.1016/S0022-510X(02)00087-4. PubMed DOI

Mishizen-Eberz A.J., Rissman R.A., Carter T.L., Ikonomovic M.D., Wolfe B.B., Armstrong D.M. Biochemical and molecular studies of NMDA receptor subunits NR1/2A/2B in hippocampal subregions throughout the progression of Alzheimer disease pathology. Neurobiol. Dis. 2004;15:80–92. doi: 10.1016/j.nbd.2003.09.016. PubMed DOI

Hynd M.R., Scott H.L., Dodd P.R. Differential expression of N-methyl-d-aspartate receptor NR2 isoforms in Alzheimer’s disease. J. Neurochem. 2004;90:913–919. doi: 10.1111/j.1471-4159.2004.02548.x. PubMed DOI

Texido L., Martin-Satue M., Alberdi E., Solsona C., Matute C. Amyloid β peptide oligomers directly activate NMDA receptors. Cell Calcium. 2011;49:184–190. doi: 10.1016/j.ceca.2011.02.001. PubMed DOI

Ronicke R., Mikhaylova M., Ronicke S., Meinhardt J., Schroder U.H., Fandrich M., Reiser G., Kreutz M.R., Reymann K.G. Early neuronal dysfunction by amyloid β oligomers depends on activation of NR2B-containing NMDA receptor. Neurobiol. Aging. 2011;32:2219–2228. doi: 10.1016/j.neurobiolaging.2010.01.011. PubMed DOI

Allyson J., Dontigny E., Auberson Y., Cyr M., Massicotte G. Blockade of NR2A-containing NMDA receptors induces tau phosphorylation in rat hippocampal slices. Neural Plast. 2010;2010 doi: 10.1155/2010/340168. PubMed DOI PMC

Petrasek T., Skurlova M., Maleninska K., Vojtechova I., Kristofikova Z., Matuskova H., Sirova J., Vales K., Ripova D., Stuchlik A. A rat model of Alzheimer’s disease based on Abeta42 and pro-oxidative substances exhibits cognitive deficit and alterations in glutamatergic and cholinergic neurotransmitter systems. Front. Aging Neurosci. 2016;8:83. doi: 10.3389/fnagi.2016.00083. PubMed DOI PMC

Shinohara Y., Hirase H., Watanabe M., Itakura M., Takahashi M., Shigemoto R. Left-right asymmetry of the hippocampal synapses with differential subunit allocation of glutamate receptors. Proc. Natl. Acad. Sci. USA. 2008;105:19498–19503. doi: 10.1073/pnas.0807461105. PubMed DOI PMC

Kristofikova Z., Ricny J., Ort M. Aging and lateralization of the rat brain on a biochemical level. Neurochem. Res. 2010;35:1138–1146. doi: 10.1007/s11064-010-0165-8. PubMed DOI

Kalinchuk A.V., Stenberg D., Rosenberg P.A., Porkka-Heiskanen T. Inducible, and neuronal nitric oxide synthases (NOS) have complementary roles in recovery sleep induction. Eur. J. Neurosci. 2006;24:1443–1456. doi: 10.1111/j.1460-9568.2006.05019.x. PubMed DOI

Kalinchuk A.V., McCarley R.W., Porkka-Heiskanen T., Basheer R. Sleep deprivation triggers inducible nitric oxide-dependent nitric oxide production in wake-active basal forebrain neurons. J. Neurosci. 2010;30:13254–13264. doi: 10.1523/JNEUROSCI.0014-10.2010. PubMed DOI PMC

Kalinchuk A.V., Porkka-Heiskanen T., McCarley R.W., Basheer R. Cholinergic neurons of the basal forebrain mediate biochemical and electrophysiological mechanisms underlaying sleep homeostasis. Eur. J. Neurosci. 2015;41:182–195. doi: 10.1111/ejn.12766. PubMed DOI PMC

Cespuglio R., Amrouni D., Meiller A., Buguet A., Gautier-Sauvigne S. Nitric oxide in the regulation of the sleep-wake states. Sleep Med. Rev. 2012;16:265–279. doi: 10.1016/j.smrv.2012.01.006. PubMed DOI

Sauvet F., Florence G., Van Beers P., Drogou C., Lagrume C., Chaumes C., Ciret S., Leftheriotis G., Chennaoui M. Total sleep deprivation alters endothelial function in rats: A nonsympathetic mechanism. Sleep. 2014;37:465–473. doi: 10.5665/sleep.3476. PubMed DOI PMC

Rytkonen K.M., Wigren H.K., Kostin A., Porkka-Heiskanen T., Kalinchuk A.V. Nitric oxide-mediated recovery sleep is attenuated with aging. Neurobiol. Aging. 2010;31:2011–2019. doi: 10.1016/j.neurobiolaging.2008.10.006. PubMed DOI

Kristofikova Z., Kozmikova I., Hovorkova P., Ricny J., Zach P., Majer E., Klaschka J., Ripova D. Lateralization of hippocampal nitric oxide mediator system in people with Alzheimer disease, multi-infarct dementia and schizophrenia. Neurochem. Int. 2008;53:118–125. doi: 10.1016/j.neuint.2008.06.009. PubMed DOI

Kristofikova Z., Stastny F., Bubenikova V., Druga R., Klaschka J., Spaniel F. Age- and sex-dependent laterality of rat hippocampal cholinergic system in relation to animal models of neurodevelopmental and neurodegenerative disorders. Neurochem. Res. 2004;29:671–680. doi: 10.1023/B:NERE.0000018837.27383.ff. PubMed DOI

Perusquia M., Greenway C.D., Perkins L.M., Stallone J.N. Systemic hypotensive effects of testosterone are androgen structure-specific and neuronal nitric oxide synthase-dependent. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2015;309:189–195. doi: 10.1152/ajpregu.00110.2015. PubMed DOI PMC

Moreau K.L. Modulatory influence of sex hormones on vascular aging. Am. J. Physiol. Heart Circ. Physiol. 2019 doi: 10.1152/ajpheart.00745.2017. PubMed DOI PMC

Ganguly P., Holland F.H., Brenhouse H.C. Functional uncoupling NMDAR NR2A subunit from PSD-95 in the prefrontal cortex: Effects on behavioral dysfunction and parvalbumin loss after early-life stress. Neuropsychopharmacology. 2015;40:2666–2675. doi: 10.1038/npp.2015.134. PubMed DOI PMC

Martisova E., Solas M., Horrillo I., Ortega J.E., Meana J.J., Tordera R.M., Ramirez M.J. Long-lasting effects of early-life stress on glutamatergic/GABAergic circuitry in the rat hippocampus. Neuropharmacology. 2012;62:1944–1953. doi: 10.1016/j.neuropharm.2011.12.019. PubMed DOI

Chauhan P.S., Misra U.K., Kalita J. A study of glutamate levels, NR1, NR2A, NR2B receptors and oxidative stress in a rat model of Japanese encephalitis. Physiol. Behav. 2017;171:256–267. doi: 10.1016/j.physbeh.2017.01.028. PubMed DOI

Costa-Nunes J., Zubareva O., Araujo-Correia M., Valenca A., Schroeter C.A., Pawluski J.L., Vignisse J., Steinbusch H., Hermes D., Phillipines M., et al. Altered emotionality, hippocampus-dependent performance and expression of NMDA receptor subunit mRNAs in chronically stressed mice. Stress. 2014;17:108–116. doi: 10.3109/10253890.2013.872619. PubMed DOI

Christie M.A., McKenna J.T., Connolly N.P., McCarley R.W., Strecker R.E. 24 h of sleep deprivation in the rat increases sleepiness and decreases vigilance: Introduction of the rat-psychomotor vigilance task. J. Sleep Res. 2008;17:376–384. doi: 10.1111/j.1365-2869.2008.00698.x. PubMed DOI PMC