It has been suggested that Nogo-A, a myelin-associated protein, could play a role in the pathogenesis of schizophrenia and that Nogo-A-deficient rodents could serve as an animal model for schizophrenic symptoms. Since changes in brain laterality are typical of schizophrenia, we investigated whether Nogo-A-deficient rats showed any signs of disturbed asymmetry in cortical N-methyl-d-aspartate (NMDA) receptor-nitric oxide synthase (NOS) pathway, which is reported as dysfunctional in schizophrenia. In particular, we measured separately in the right and left hemisphere of young and old Nogo-A-deficient male rats the expression of NMDA receptor subunits (NR1, NR2A, and NR2B in the frontal cortex) and activities of NOS isoforms [neuronal (nNOS), endothelial (eNOS), and inducible (iNOS) in the parietal cortex]. In young controls, we observed right/left asymmetry of iNOS activity and three positive correlations (between NR1 in the left and NR2B laterality, between NR2B in the right and left sides, and between NR1 in the right side and nNOS laterality). In old controls, we found bilateral decreases in NR1, an increase in NR2B in the right side, and two changes in correlations in the NR1-nNOS pathway. In young Nogo-A-deficient rats, we observed an increase in iNOS activity in the left hemisphere and two changes in correlations in NR1-nNOS and NR2A-eNOS, compared to young controls. Finally, we revealed in old Nogo-A-deficient animals, bilateral decreases in NR1 and one change in correlation between eNOS-iNOS, compared to old controls. Although some findings from schizophrenic brains did not manifest in Nogo-A-deficient rats (e.g., no alterations in NR2B), others did (e.g., alterations demonstrating accelerated aging in young but not old animals, those occurring exclusively in the right hemisphere in young and old animals and those suggesting abnormal frontoparietal cortical interactions in young animals).

Prague Psychiatric Centre Prague Czech Republic

Zobrazit více v PubMed

Budel S., Padukkavidana T., Liu B. P., Feng Z., Hu F., Johnson S., et al. (2008). Genetic variants of Nogo-66 receptor with possible association to schizophrenia block myelin inhibition of axon growth. J. Neurosci. 28, 13161–1317210.1523/JNEUROSCI.3828-08.2008 PubMed DOI PMC

Clinton S. M., Haroutunian V., Meador-Woodruff J. H. (2006). Up-regulation of NMDA receptor subunit and post-synaptic density protein expression in the thalamus of elderly patients with schizophrenia. J. Neurochem. 98, 1114–112510.1111/j.1471-4159.2006.03954.x PubMed DOI

Clinton S. M., Meador-Woodruff J. H. (2004). Abnormalities of the NMDA receptor and associated intracellular molecules in the thalamus in schizophrenia and bipolar disorder. Neuropharmacology 29, 1353–1362 PubMed

Connelly L., Madhani M., Hobbs A. J. (2005). Resistance to endotoxic shock in endothelial nitric-oxide synthase (eNOS) knock-out mice. J. Biol. Chem. 280, 10040–1004610.1074/jbc.M411991200 PubMed DOI

Coon H., Myles-Worsley M., Tiobech J., Hoff M., Rosenthal J., Bennett P., et al. (1998). Evidence for a chromosome 2p13-14 schizophrenia susceptibility locus in families from Palau, Micronesia. Mol. Psychiatry 3, 521–52710.1038/sj.mp.4000453 PubMed DOI

Davis K. L., Stewart D. G., Friedman J. I., Buchsbaum M., Harvey P. D., Hof P. R., et al. (2003). White matter changes in schizophrenia: evidence for myelin-related dysfunction. Arch. Gen. Psychiatry 60, 443–45610.1001/archpsyc.60.6.553 PubMed DOI

Dodd D. A., Niederoest B., Bloechlinger S., Dupuis L., Leoffler J. P., Schwab M. E. (2005). Nogo-A, -B, and -C are found on the cell surface and interact together in many different cell types. J. Biol. Chem. 280, 12494–1250210.1074/jbc.M411827200 PubMed DOI

Gao X. M., Sakai K., Roberts R. C., Conley R. R., Dean B., Tamminga C. A. (2000). Ionotropic glutamate receptors and expression of N-methyl-d-aspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia. Am. J. Psychiatry 157, 1141–114910.1176/appi.ajp.157.7.1141 PubMed DOI

Gil V., Nicolas O., Mingorance A., Ureña J. M., Tang B. L., Hirata T., et al. (2006). Nogo-A expression in the human hippocampus in normal aging and in Alzheimer disease. J. Neuropathol. Exp. Neurol. 65, 433–44410.1097/01.jnen.0000222894.59293.98 PubMed DOI

Hsu R., Woodroffe A., Lai W. S., Cook M. N., Mukai J., Dunning J. P., et al. (2007). Nogo receptor 1 (RTN4R) as a candidate gene for schizophrenia: analysis using human and mouse genetic approaches. PLoS ONE 2:1234.10.1371/journal.pone.0000395 PubMed DOI PMC

Jitoku D., Hattori E., Iwayama Y., Yamada K., Toyota T., Kikuchi M., et al. (2011). Association study of Nogo-related genes with schizophrenia in a Japanese case-control sample. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156, 581–59210.1002/ajmg.b.31199 PubMed DOI

Kamida T., Takeda Y., Fujiki M., Abe T., Abe E., Kobayashi H. (2007). Nitric oxide synthase and NMDA receptor expressions in cavernoma tissues with epileptogenesis. Acta Neurol. Scand. 116, 368–37310.1111/j.1600-0404.2007.00885.x PubMed DOI

Kawakami R., Shinohara Y., Kato Y., Sugiyama H., Shigemoto R., Ito I. (2003). Asymmetrical allocation of NMDA receptor ε2 subunits in hippocampal circuitry. Science 300, 990–99410.1126/science.1082609 PubMed DOI

Kim J. J., Kwon J. S., Park H. J., Youn T., Kang D. H., Kim M. S., et al. (2003). Functional disconnection between the prefrontal and parietal cortices during working memory processing in schizophrenia: a [15O]H2O PET study. Am. J. Psychiatry 160, 919–92310.1176/appi.ajp.160.5.919 PubMed DOI

Kirpatrick B., Messias E., Harvey P. D., Fernandez-Egea E., Bowie C. R. (2008). Is schizophrenia a syndrome of accelerated aging? Schizophr. Bull. 34, 1024–103210.1093/schbul/sbm140 PubMed DOI PMC

Krištofiková Z., Kozmiková I., Hovorková P., Rícný J., Zach P., Majer E., et al. (2008). Lateralization of hippocampal nitric oxide mediator system in people with Alzheimer disease, multi-infarct dementia and schizophrenia. Neurochem. Int. 53, 118–12510.1016/j.neuint.2008.06.009 PubMed DOI

Krištofiková Z., Rícný J., Ort M., Rípová D. (2010). Aging and lateralization of the rat brain on a biochemical level. Neurochem. Res. 35, 1138–114610.1007/s11064-010-0165-8 PubMed DOI

Krištofiková Z., Štastný F., Bubeníková V., Druga R., Klaschka J., Španiel F. (2004). Age- and sex-dependent laterality of rat hippocampal cholinergic system in relation to animal models of neurodevelopmental and neurodegenerative disorders. Neurochem. Res. 29, 671–68010.1023/B:NERE.0000018837.27383.ff PubMed DOI

Kubota M., Miyata J., Yoshida H., Hirao K., Fujiwara H., Kawada R., et al. (2011). Age-related cortical thinning in schizophrenia. Schizophr. Res. 125, 21–2910.1016/j.schres.2010.10.004 PubMed DOI

Li D., He L. (2007). Association study between the NMDA receptor 2B subunit gene (GRIN2B) and schizophrenia: a HuGE review and meta-analysis. Genet. Med. 9, 4–810.1097/01.gim.0000250507.96760.4b PubMed DOI

Magnusson K. R., Nelson S. E., Young A. B. (2002). Age-related changes in the protein expression of subunits of the NMDA receptor. Brain Res. Mol. Brain Res. 99, 40–4510.1016/S0169-328X(01)00344-8 PubMed DOI

Mathis C., Schröter A., Thallmair M., Schwab M. E. (2010). Nogo-A regulates neural precursor migration in the embryonic mouse cortex. Cereb. Cortex 20, 2380–239010.1093/cercor/bhp307 PubMed DOI PMC

Novak G., Kim D., Seeman P., Tallerico T. (2002). Schizophrenia and Nogo: elevated mRNA in cortex, and high prevalence of a homozygous CAA insert. Brain Res. Mol. Brain Res. 107, 183–18910.1016/S0169-328X(02)00492-8 PubMed DOI

Novak G., Tallerico T. (2006). Nogo A, B and C expression in schizophrenia, depression and bipolar frontal cortex, and correlation of Nogo expression with CAA/TATC polymorphism in 3′UTR. Brain Res. 1120, 161–17110.1016/j.brainres.2006.08.071 PubMed DOI

Nudmamud-Thanoi S., Reynolds G. P. (2004). The NR1 subunit of the glutamate/NMDA receptor in the superior temporal cortex in schizophrenia and affective disorders. Neurosci. Lett. 372, 173–17710.1016/j.neulet.2004.09.035 PubMed DOI

Ocklenburg S., Arning L., Hahn C., Gerding W. M., Epplen J. T., Güntürkün O., et al. (2011). Variation in the NMDA receptor 2B subunit gene GRIN2B is associated with differential language lateralization. Behav. Brain Res. 225, 284–28910.1016/j.bbr.2011.07.042 PubMed DOI

Rapoport J. L., Addington A. M., Frangou S., Psych M. R. C. (2005). The neurodevelopmental model of schizophrenia: update 2005. Mol. Psychiatry 10, 434–44910.1038/sj.mp.4001642 PubMed DOI

Shaw S. H., Kelly M., Smith A. B., Shields G., Hopkins P. J., Loftus J., et al. (1998). A genome-wide search for schizophrenia susceptibility genes. Am. J. Med. Genet. 81, 364–37610.1002/(SICI)1096-8628(19980907)81:5<364::AID-AJMG4>3.0.CO;2-T PubMed DOI

Simonen M., Pedersen V., Weinmann O., Schnell L., Buss A., Ledermann B., et al. (2003). Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury. Neuron 38, 201–21110.1016/S0896-6273(03)00226-5 PubMed DOI

Sinibaldi L., De Luca A., Bellacchio E., Conti E., Pasini A., Paloscia C., et al. (2004). Mutations of the Nogo-66 receptor (RTN4R) gene in schizophrenia. Hum. Mutat. 24, 534–53510.1002/humu.9290 PubMed DOI

Tan E. C., Chong S. A., Wang H., Lim E. C. P., Teo Y. Y. (2005). Gender-specific association of insertion/deletion polymorphisms in the nogo gene and chronic schizophrenia. Brain Res. Mol. Brain Res. 139, 212–21610.1016/j.molbrainres.2005.05.010 PubMed DOI

Tang B., Chang W., Lanigan C. M., Dean B., Sutcliffe J. G., Thomas E. A. (2009). Normal human aging and early-stage schizophrenia share common molecular profiles. Aging Cell 8, 339–34210.1111/j.1474-9726.2009.00468.x PubMed DOI PMC

Tews B., Schönig K., Arzt M. E., Clementi S., Rioult-Pedotti M. S., Zemmar A., et al. (2013). Synthetic miRNA-mediated downregulation of Nogo-A in transgenic rats reveals its role as regulator of plasticity, learning and memory. Proc. Natl. Acad. Sci. U.S.A. 110, 6583–658810.1073/pnas.1217665110 PubMed DOI PMC

Toga A. W., Thompson P. M. (2003). Mapping brain asymmetry. Nat. Neurosci. 4, 37–4810.1038/nrn1009 PubMed DOI

Turnock-Jones J. J., Jennings C. A., Robbins M. J., Cluderay J. E., Cilia J., Reid J. L., et al. (2009). Increased expression of the NR2A NMDA receptor subunit in the prefrontal cortex of rats reared in isolation. Synapse 63, 836–84610.1002/syn.20665 PubMed DOI

Vrajová M., Štastný F., Horácek J., Lochman J., Šerý O., Peková S., et al. (2010). Expression of the hippocampal receptor GluN1 subunit and its splicing isoforms in schizophrenia: postmortem study. Neurochem. Res. 35, 994–100210.1007/s11064-010-0145-z PubMed DOI

Willi R., Schwab M. E. (2013). Nogo and Nogo receptor: relevance to schizophrenia? Neurobiol. Dis. 54, 150–15710.1016/j.nbd.2013.01.011 PubMed DOI

Willi R., Weinmann O., Winter C., Klein J., Sohr R., Schnell L., et al. (2010). Constitutive genetic deletion of the growth regulator Nogo-A induces schizophrenia-related endophenotypes. J. Neurosci. 30, 556–56710.1523/JNEUROSCI.4393-09.2010 PubMed DOI PMC

Woo T. U. W., Walsh J. P., Benes F. M. (2004). Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-d-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder. Arch. Gen. Psychiatry 61, 649–65710.1001/archpsyc.61.7.649 PubMed DOI

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

Differences Between Tg2576 and Wild Type Mice in the NMDA Receptor-Nitric Oxide Pathway After Prolonged Application of a Diet High in Advanced Glycation End Products

Cognitive deficits in schizophrenia and other neuropsychiatric disorders: convergence of preclinical and clinical evidence

Nogo-A-deficient Transgenic Rats Show Deficits in Higher Cognitive Functions, Decreased Anxiety, and Altered Circadian Activity Patterns