N-Methyl-d-Aspartate Receptor – Nitric Oxide Synthase Pathway in the Cortex of Nogo-A-Deficient Rats in Relation to Brain Laterality and Schizophrenia

Abstract

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).

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

“…Experimental results support the involvement of the NMDA receptor-NO pathway in the pathogenesis of AD [e.g., 10,11] and demonstrate marked changes in this system dependent on the stage of dementia [13]. Moreover, the pathway seems to be influenced by chronic hyperglycaemia or diabetes [for a review, see 14].…”

“…The experiments were performed in accordance with our previous study [11]. Briefly, 200 ll of frozen homogenates were homogenized in 200 ll of lysis buffer (320 mM sucrose, 10 mM Tris, 0.2 mM ethylenediaminetetraacetic acid (EDTA), 2 mM phenylmethanesulfonyl fluoride (PMSF), 1 mM 2-mercaptoethanol and 0.05 % protease inhibitor cocktail; pH 7.4).…”

“…The method was performed in accordance with our previous studies [10,11] leupeptin; pH 7.4] and centrifuged at 1200g for 10 min at 4°C. Supernatants were added to reaction buffer [centrifugation buffer containing also 200 lM b-nicotinamide adenine dinucleotide phosphate, 50 lM tetrahydrobiopterin and 4.6 lM [ 14 C] arginine (American Radiolabeled Chemicals, Inc.,)] and incubated for 30 min at 37°C.…”

“…It is wellknown that the stimulation of NMDA receptors activates the synthesis of NO via this pathway [10,11]. Functional interactions have been reported, especially between the NR1 subunit of NMDA receptor and nNOS, but also between the NR2A or NR2B subunits and the eNOS/iNOS isoforms [e.g., 12].…”

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

“…The study shows effects of psilocin, an active serotonergic hallucinogen of Psylocibe mushrooms, on the acquisition, retrieval, and consolidation of memory in two spatial navigation tasks. Another three studies (Kristofikova et al, 2013;Enkel et al, 2014;Petrasek et al, 2014) examined a very promising model of schizophrenia based on transgenic rats with reduced activity of Nogo-A (a protein inhibiting axonal growth). These rats exert neurodevelopmental abnormalities, and disruptions were found in their brain biochemistry, motivation, higher cognitive functions, and circadian rhythms.…”