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Chronic Neuroinflammation and Altered Inflammatory Responses in a Mouse Model of Autism

Thursday, 2 May 2013: 09:00-13:00
Banquet Hall (Kursaal Centre)
L. Lucchina, N. Kazlauskas, M. Campolongo and A. M. Depino, IFIByNE, UBA-CONICET, Buenos Aires, Argentina
Background: Several reports have associated peripheral and central alterations in the inflammatory and immune responses with autism spectrum disorders (ASD). However, the consequences of these inflammatory processes on the behavioral symptoms of ASD have not been extensively studied.

Objectives: Our aims are (1) to evaluate the extent of neuroinflammation in a mouse model of ASD, and (2) to evaluate whether the inflammatory response is altered in this model.

Methods: We injected pregnant mice with 400 or 600 mg/kg valproic acid (VPA), at gestational day (GD) 12.5. We then evaluated social interaction and anxiety-related behaviors of the offspring. Moreover, we evaluated the inflammatory response to a peripheral LPS challenge. 2 hs after a 25 mg/kg intraperitoneal LPS injection, we measured plasma corticosterone and the expression of cytokines in the spleen and in regions of the brain relevant to ASD (the cerebellum, the cortex and the hippocampus). Furthermore, we evaluated the number of microglial cells and the area occupied by astrocytes in those same areas.

Results: We confirmed that prenatal exposure to VPA at GD12.5 results in reduced social interaction in adulthood, in the F1 hybrid offspring. Moreover, VPA exposure results in increased anxiety-related behavior. VPA-exposed mice show an exacerbated inflammatory response in adulthood. 2 hs after the LPS injection, plasma corticosterone levels are higher in VPA mice than in controls. Moreover, LPS induces the expression of IL-1β, IL-6 and TNF-α in the spleen, but the increase of IL-6 is significantly higher in animals prenatally exposed to VPA. When we evaluated the central inflammatory response to a peripheral stimulus, we also found evidence of an exacerbated response. IL-1β and IL-6 are specifically induced in the cortex of VPA-exposed animals challenged with LPS, and not in control animals. Moreover, although LPS induced the expression of IL-6 and TNF-α in all groups, this increment was significantly higher in animals prenatally exposed to VPA. Finally, animals prenatally exposed to 600 mg/kg VPA have more microglial cells in the hilus of the dentate gyrus and in the CA1 of the hippocampus. Animals prenatally exposed to 600 mg/kg VPA have more microglial cells in the cerebellum, but they show no differences in the number of these cells after a peripheral inflammatory challenge.

Conclusions: Our results further validate the VPA mouse model of ASD, showing that the reduction of social interaction is independent of the genetic background of the animals. On the contrary, the effect of VPA on anxiety-related behaviors appears to be modulated by genetic factors. We found that animals exposed to VPA show an exacerbated response to an inflammatory stimulus, evidenced as increased activation of the hypothalamus-pituitary-adrenal axis, and increased expression of pro-inflammatory cytokines in the periphery and in certain, specific regions of the brain. In addition, we found evidence of neuroinflammation in the cerebellum of VPA-exposed animals. These results show that the VPA model of ASD also models the neuroinflammation and the alterations in the inflammatory response previously documented in ASD patients.

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