Impairments of N-methyl-D-aspartate receptor (NMDAR) activity have been implicated in several neuropsychiatric disorders, with pharmacological inhibition of NMDAR-mediated currents and associated neurobehavioral changes considered as a model of schizophrenia. We analyzed the effects of brief and long-term exposure of rat cortical cultures to the most prevalent endogenous modulators of NMDAR (kynurenic acid, pregnenolone sulfate, spermidine, and zinc) on neuronal viability, stimulation-induced release of glutamate, and dendritic morphology with synaptic density. Both, glutamate release and neuronal viability studies revealed no difference between the test and control groups. No differences were also observed in the number of dendritic branching and length, or density of synaptic connections and neuronal soma size. Comparison of the extent of dendritic projections and branching patterns, however, revealed enhanced distal arborization with the expansion of the dendritic area under prolonged treatment of cultures with physiological concentrations of NMDAR modulators, with differences reaching significance in spermidine and pregnenolone sulfate tests. Measurements of the density of glutamatergic synapses showed consistency across all neuronal groups, except those treated with pregnenolone sulfate, which showed a reduction of PSD-95-positive elements. Overall, our data suggest that constitutive glutamatergic activity mediated by NMDAR controls the dendritic field expansion and can influence the integrative properties of cortical neurons.

• Klíčová slova
• Cortical thinning, Dendritic morphology, Glutamate release, Intrinsic excitability, Neuroplasticity, Neurosteroids, Polyamines, psd95,
• MeSH
• glutamáty MeSH
• krysa rodu Rattus MeSH
• neurony metabolismus   MeSH
• receptory N-methyl-D-aspartátu * metabolismus   MeSH
• signální transdukce MeSH
• spermidin * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• glutamáty MeSH
• receptory N-methyl-D-aspartátu * MeSH
• spermidin * MeSH

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.

• Klíčová slova
• NMDA receptor subunits, acute and chronic sleep deprivation, aging, brain lateralization, cortex, nitric oxide synthases,
• MeSH
• Alzheimerova nemoc epidemiologie   etiologie   MeSH
• krysa rodu Rattus MeSH
• membránové glykoproteiny genetika   metabolismus   MeSH
• mozková kůra metabolismus   MeSH
• oxid dusnatý metabolismus   MeSH
• potkani Wistar MeSH
• receptory N-methyl-D-aspartátu genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• rizikové faktory MeSH
• signální transdukce * MeSH
• spánková deprivace metabolismus   patofyziologie   MeSH
• stárnutí metabolismus   MeSH
• synthasa oxidu dusnatého metabolismus   MeSH
• věkové faktory MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• Grin3a protein, rat MeSH Prohlížeč
• membránové glykoproteiny MeSH
• N-methyl D-aspartate receptor subtype 2A MeSH Prohlížeč
• NR2B NMDA receptor MeSH Prohlížeč
• oxid dusnatý MeSH
• receptory N-methyl-D-aspartátu MeSH
• synthasa oxidu dusnatého MeSH

It has been suggested that advanced glycation end (AGE) products, via cognate receptor activation, are implicated in several diseases, including Alzheimer's disease. The NMDA receptor-nitric oxide pathway appears to be influenced by AGE products and involved in the pathogenesis of this type of dementia. In this study, C57BL/6J (WT) and transgenic (Tg2576) mice expressing human mutant amyloid precursor protein were kept on prolonged (8 months) diets containing regular or high amounts of AGE products. After the decapitation of 11-months old mice, brain tissue analyses were performed [expressions of the NR1, NR2A and NR2B subunits of NMDA receptors, activities of neuronal, endothelial and inducible nitric oxide synthase (nNOS, eNOS and iNOS)]. Moreover, levels of malondialdehyde and of human amyloid β 1-42 were estimated. We found increased activity of nNOS in WT mice maintained on a high compared to regular AGE diet; however, no similar differences were found in Tg2576 mice. In addition, we observed an increase in NR1 expression in Tg2576 compared to WT mice, both kept on a diet high in AGE products. Correlation analyses performed on mice kept on the regular AGE diet supported close links between particular subunits (NR2A-NR2B, in WT as well as in Tg2576 mice), between subunits and synthase (NR2A/NR2B-nNOS, only in WT mice) or between particular synthases (nNOS-iNOS, only in WT). Correlation analysis also revealed differences between WT mice kept on both diets (changed correlations between NR2A/NR2B-nNOS, between nNOS-eNOS and between eNOS-iNOS). Malondialdehyde levels were increased in both Tg2576 groups when compared to the corresponding WT mice, but no effects of the diets were observed. Analogously, no significant effects of diets were found in the levels of soluble or insoluble amyloid β 1-42 in Tg2576 mice. Our results demonstrate that prolonged ingestion of AGE products can influence the NMDA receptor-nitric oxide pathway in the brain and that only WT mice, not Tg2576 mice, are able to maintain homeostasis among subunits and synthases or among particular synthases. The prolonged application of AGE products enhanced differences between 11-months old Tg2576 and WT mice regarding this pathway. Observed differences in the pathway between WT mice kept on regular or high AGE diets suggest that the prolonged application of a diet low in AGE products could have beneficial effects in older or diabetic people and perhaps also in people with Alzheimer's disease.

• MeSH
• dietní proteiny aplikace a dávkování   MeSH
• lidé MeSH
• mozek metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši transgenní MeSH
• myši MeSH
• oxid dusnatý metabolismus   MeSH
• produkty pokročilé glykace aplikace a dávkování   MeSH
• receptory N-methyl-D-aspartátu metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• dietní proteiny MeSH
• oxid dusnatý MeSH
• produkty pokročilé glykace MeSH
• receptory N-methyl-D-aspartátu MeSH

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).

• Klíčová slova
• aging, animal model of schizophrenia, brain laterality, cortex, myelin-associated protein,
• Publikační typ
• časopisecké články MeSH

It has been suggested that the lateralization of the human brain underlies hemispheric specialization and that it can be observed also on a biochemical level. Biochemical laterality appears to be a basis of volumetric or functional asymmetry but direct relationships among them are still unclear. Moreover, age-related differences between the right and left hemispheres are not well documented in various rat strains. In the current study, biochemical markers sensitive to Alzheimer disease (activities of high-affinity choline uptake and of nitric oxide synthases, expression of 17beta-hydroxysteroid dehydrogenase type 10) were estimated in both hemispheres of young and old male Wistar/Long Evans rats. Our experiments indicate (1) differences in some biochemical markers between young Wistar and Long Evans rats (the activities of endothelial nitric oxide synthase are higher in Long Evans and those of citrate synthase in Wistar rats), (2) more similar brain asymmetry of healthy human/young Wistar brains when compared to those of young Long Evans, (3) the decrease in asymmetry of the physiologically left/right lateralized biomarker during aging (the activity of the high-affinity choline uptake decreases more markedly in the left side of old Wistar rats) in accordance with the HAROLD model, (4) the age-related shift to reversed left/right asymmetry of the physiologically right/left lateralized biomarker (the activity of inducible nitric oxide synthase increases especially in the left side of old Long Evans rats), and finally (5) age-related differences in physiologically unlateralized biomarkers between Wistar and Long Evans rats (changes in the activities of neural/endothelial nitric oxide synthases or in expression of 17beta-hydroxysteroid dehydrogenase type 10 are more asymmetrical in old Wistar when compared to rather bilateral alterations of old Long Evans animals). It seems that the physiological lateralization of the human or rat brains on a biochemical level and their age-related alterations are dependent on biomarker type/function. By our opinion, it is difficult, perhaps impossible, to make one simple universal model, at least on a biochemical level. Since lateral analyses are of sufficient sensitivity to reveal subtle links, we recommend using Wistar rather than Long Evans rats in modeling of diseases accompanied by alterations in brain asymmetry.

• MeSH
• 17-hydroxysteroidní dehydrogenasy metabolismus   MeSH
• Alzheimerova nemoc metabolismus   MeSH
• biologické markery metabolismus   MeSH
• cholin metabolismus   MeSH
• citrátsynthasa metabolismus   MeSH
• druhová specificita MeSH
• funkční lateralita MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• mozek metabolismus   MeSH
• potkani Long-Evans MeSH
• potkani Wistar MeSH
• stárnutí metabolismus   MeSH
• synthasa oxidu dusnatého, typ I metabolismus   MeSH
• synthasa oxidu dusnatého, typ II metabolismus   MeSH
• synthasa oxidu dusnatého, typ III metabolismus   MeSH
• velký mozek metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• 17-hydroxysteroidní dehydrogenasy MeSH
• biologické markery MeSH
• cholin MeSH
• citrátsynthasa MeSH
• synthasa oxidu dusnatého, typ I MeSH
• synthasa oxidu dusnatého, typ II MeSH
• synthasa oxidu dusnatého, typ III MeSH

There is accumulating evidence that disturbances in N-methyl-D: -aspartate receptor (NMDA-R) functioning are associated with the pathogenesis of schizophrenia. To assess actual changes in the expression of the GluN1 subunit and its isoforms, we measured absolute differences in the levels of mRNA/protein for panGluN1 (eight isoforms altogether) as well as the mRNA individual isoforms in the postmortem left/right hippocampus of patients with schizophrenia in comparison with non-psychiatric subjects. There were no significant differences in the panGluN1 subunit mRNA expression, but the absolute left/right differences were much more pronounced in the patients with schizophrenia. Protein levels of the GluN1 subunit in the left hippocampus in male schizophrenic patients were lower than controls. The expression of the NR1-4b isoform was attenuated in the left, whereas the NR1-2b was reduced in the right hippocampus of schizophrenic patients. Isoforms associated with the efficiency of NMDA-induced gene expression and with phosphorylation occurred more commonly in schizophrenic hippocampi. In summary, our study suggests that NMDA-R hypofunction in schizophrenia might be selectively dependent on the dysregulation of GluN1 subunit expression, which exhibits a somewhat different expression in the left/right hippocampus of psychotic patients.

• MeSH
• alternativní sestřih MeSH
• lidé MeSH
• messenger RNA biosyntéza   genetika   MeSH
• podjednotky proteinů biosyntéza   genetika   MeSH
• protein - isoformy biosyntéza   genetika   MeSH
• receptory N-methyl-D-aspartátu biosyntéza   genetika   MeSH
• schizofrenie metabolismus   MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• messenger RNA MeSH
• podjednotky proteinů MeSH
• protein - isoformy MeSH
• receptory N-methyl-D-aspartátu MeSH