Determinação de alterações comportamentais e mecanismos neuroinflamatórios no modelo neurodesenvolvimental de esquizofrenia induzida por desafio imune em ratos neonatos

Abstract

Schizophrenia is a major mental disorder. This disorder can impair thought processes, volition, perception, affect and social interaction. The causes of schizophrenia are still unknown, ranging from genetic influences, environmental factors, and dysfunction of brain areas, pathophysiological alterations and neurodevelopmental impairments. This work aims to determine the behavioral and neuroinflammatory changes in a neurodevelopment model of schizophrenia induced by neonatal immune challenge induced by Poly I:C in rats. For this, Wistar rats of both sex in the periods of 5-7 days (neonates), 35 days (adolescents), 60 days (young adults) and 74 days (adulthood) were used. To determine the preventive and theraputical effects of Clozapine, this antipsychotic was administered to adolescent and adult rats, respectively. The behavioral data was presented as mean ± standard error of the mean (SEM) and analyzed by two-way ANOVA followed by Bonferroni test as post-hoc test. The Y-maze test, in turn, was analyzed by one-way ANOVA followed by Student Newman Keuls. Values were considered significant when p <0.05. The results showed that the administration of Poly I: C at a dose of 2.0 mg/kg to neonates from 5-7 post natal days was able to induce schizophrenia as observed in young adults and adulthood by decreases in the pencentage of prepulse inhibition (PPI) of the startle reflex. These animals also presented working memory deficits noticed by increases in the number of error displayed in the Y maze test. Adolescent poly I:C treated animals did not present significant behavioral alterations as compared to adult poly I:C animals. Evaluation of inducible nitric oxide synthase (iNOS) by immunohistochemical technique in rat brain tissues (PFC, hippocampus and striatum), showed an intense diffuse staining of iNOS in the tissues of the PFC and the striatum and a strong to moderate staining in the hippocampus of poly I:C adult animals when compared to the adult control group. However, a light staining was observed in adolescent animals when compared to other groups. There were differences in the intensity of staining between adolescent and adult Poly I: C animals, where the adult group showed higher intensity staining. Treatment with clozapine, in turn, decreased the staining of iNOS in some areas such as the hippocampus and PFC, being less evident in other as the striatum. These different results regarding the intensity of immunohistochemical stainning can be explained by the difference of dopaminergic receptors of the brain tissues studied. It is believed that these systems are modulated by nitric oxide. The evaluation by immunofluorescence for Iba-1 (a microglia marker) in the brain areas investigated, particularly in the hippocampus showed a decrease in the presence of ramifications and processes in the microglial cells from adult rats exposed to Poly I: C. In addition, the microglial cell bodies of the poly I:C adult rats were enlarged when compared to control adult animals, therefore indicating that adult poly I:C presented a higher microglial activation. In adolescent animals this activation was shown to be mild to moderate. Taken together, the current results showed, for the first time, an activation of microglial cells in adult animals submmited to the neonatal immune challenge accompanied by increases in iNOS staining. In addition, the atypical antipsychotic clozapine was able to revert poly I:C induced alterations indicating iNOS as a possible novel target for clozapine action.