Modelo murino do espectro autista empregando o ácido valproico durante a gravidez: mudanças comportamentais e citocinas pró-inflamatórias

Abstract

The present study evaluated, in behavioral tests, the exploratory and locomotor activities of young adult BALB/c mice that were exposed to valproic acid during pregnancy and measured their proinflammatory cytokines concentration in peripheral blood. To this end, we exposure females to males and on day 12.5 of gestation, females received 0.2 mL of VPA diluted in saline (600 mg / kg body weight) or equal volume of saline solution. The pups were weaned on the 21st postnatal day and the males were kept either in the impoverished environment of standard laboratory cages (IE) or in an enriched cage (EE). Four independent experimental groups according to experimental condition and environment (Ctrl / EE, Ctrl / IE, VPA / EE, VPA / IE) were organized. At 5 months of age, all animals were submitted to Open Field (OF), Episodic Memory (EM), Burrowing and Elevated Plus Maze (EPM) tests and had their peripheral blood collected and then perfused with saline followed by aldehyde fixatives. Two-way ANOVA revealed significant influences of experimental condition (VPA vs. Saline) and environment (EE vs IE) on behavioral outcomes and on proinflammatory cytokines peripheral concentrations. In the open field, the valproic acid groups, regardless of the environment where they were kept, reversed the natural tendency to avoid the center of the arena, F (1,54) = 5.59, p = 0.022. Similarly, in the elevated plus maze, the valproic acid groups, independent of the environment where the animals were kept, showed a significant influence on the time spent in the central platform, reducing it significantly, F (1,51) = 7.57, p = 0.0082. Two-way ANOVA also demonstrated a significant influence of the experimental condition (VPA vs. Saline) on the immune response reducing IL-1β, F (1.49) = 26.24, p <0.0001 and increasing IL-6, F (1.46) = 16.96, p = 0.0002 of the valproic acid groups. BALB/c mice exposed to valproic acid during pregnancy shows significant changes on their behavior to explore novel environments and to assess risk at adulthood, and this is associated with proinflammatory cytokines peripheral changes. Somatosensory and cognitive stimulation of environmental enrichment seems to be not enough to reverse it.