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Research into mechanisms of interaction between growth and inhibitory proteins of the CNS and behavioral expressions of healthy and disordered brain is one of the contemporary topics. A knockdown model with decreased expression of Nogo-A protein in neurons was developed on the genetic background of Sprague-Dawley wildtypes. Disruption of this inhibitory factor was hypothesized to result in behavioral abnormalities, which were studied both in young, middle age (6 months) and aged (12 months) rats.
Animals were tested in a battery of Carousel maze variants with various demands for segregation of spatial information and flexibility; animals avoided an unmarked sector of either stable or rotating arena; moreover the sector could be defined in room- or arena-frame. A shortened Carousel maze battery and Morris water maze (MWM) including one- trial matching-to-place and reversal configurations was used.
Nogo-A-deficient rats were impaired in the final phases of the Carousel maze battery but their spatial working memory tested in the MWM was intact. Middle-aged and aged groups were differently affected in the battery, but deficits in young animals were observed not to be worsened with ageing. Concept of multidirectional age-related alterations in this animal model is further supported by biochemical brain changes.
Nogo-A-deficient rats may serve as an extremely useful model of neurodevelopmental deficit, which may manifest by behavioral changes accessible to phenotyping and in-depth analysis. Relevance of this approach for animal models of neuropsychiatric models will be discussed.
It seems that schizophrenia may arise from abnormal neurodevelopment due to aberrant neuron formation and migration and that deletion of Nogo-A (a myelin associated inhibitor of regenerative fiber growth) may lead to schizophrenia-like abnormalities in animal model. Our previous studies reported a high sensitivity of lateral analyses to reveal subtle links and recommended to apply them to validate animal models of diseases accompanied by alterations in brain asymmetry.
Expressions of N-methyl-D-aspartate receptor subunits (NR1, NR2A, NR2B) and activities of subunits-associated synthases of nitric oxide (nNOS, eNOS, iNOS) were evaluated in the right and left cortex of young or old Nogo-A deficient rats.
In young controls, no marked laterality was observed in subunits/synthases excepting iNOS but correlation analyses supported links among some subunits, synthases or subunits - synthases. Drops in NR1 (bilaterally) and in NR2B (in the right side) or asymmetrical alterations in NR1 - nNOS pathway were observed in old controls. In young Nogo-A deficient rats, the increase in iNOS (in the left side) and the disruption in left NR1 - right nNOS or in right NR2A - right eNOS pathways were found. And finally in old Nogo-A deficient animals, we observed the increase in NR1 (bilaterally) and in positive correlation between right eNOS - right iNOS.
Although some changes in subunits/synthases observed in people with schizophrenia were not found in Nogo-A deficient rats, some alterations in laterality support the validity of this model.
The study was supported by MSMT (1M0517) and MZCR (MZ0PCP2005) projects.
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