CONICET | Buscador de Institutos y Recursos Humanos

Autism spectrum disorder (ASD) is one of the most severe conditions in the broad range of developmental abnormalities known as pervasive developmental disorders. Anatomical and structural brain abnormalities have been observed in autistic patients by longitudinal clinical and magnetic resonance imaging studies. One developing hypothesis imputes them to ongoing neuroinflammatory processes in the brain of ASD patients. In particular, neuropathological studies of post-mortem brain tissues from autistic patients demonstrate an active neuroinflammatory process in the cerebral cortex and white matter, characterized by astroglial activation (Vargas, D.L., et al. Ann Neurol, 2005. 57(1): p. 67-81). In line with this, many of the proposed etiological factors for autism can result in glial activation (e.g., genetic susceptibility, prenatal environmental exposures). Therefore, we hypothesize that neuroinflammation can be the common factor triggering developmental alterations of the brain. Moreover, Vargas et al. identified upregulated TGF-β1 in autistic brain tissues by protein array techniques. This anti-inflammatory cytokine was consistently high in three different brain regions: cerebellum, anterior cingulate gyrus, and middle frontal gyrus of autistic subjects. TGF-β1 has both neuroprotective and neurodegenerative functions, depending on conditions such as the duration and the local and temporal pattern of its expression. To evaluate the contribution of TGF-β1 on autism-like behavior we injected an adenoviral vector expressing TGF-β1 in the dentate gyrus of the hippocampus (Hi AdTGF-β1) or the vermis VI-VII of the cerebellum (Cer AdTGF-β1) of C57BL/6J mice. Control animals were injected with an adenoviral vector expressing Beta-galactosidase (Hi Adβgal and Cer Adβgal). Animals were behaviorally tested between weeks 2 and 3 post-adenoviral injection, when transgene expression is maximal. Hi AdTGF-β1 significantly increased the preference for the social compartment in the social approach-avoidance test. To test whether this was due to an increased response to novelty, animals were tested in an open field. No differences were observed in exploration of the open field between Hi Adβgal and Hi AdTGF-β1 animals. However, when tested in the novel object recognition paradigm, Hi AdTGF-β1 explored more both the displaced and the novel objects. This shows that hippocampal TGF-β1 overexpression results in increased response to novelty, but does not affect exploration of a novel environment. Cer AdTGF-β1 mice also showed an increase in the exploration of the social compartment, without effects on the open field. We conclude that brain TGF-β1 overexpression can alter the response to both social and non-social novelty. However, these results do not go in line with a role of the previously observed increased TGF-β1 levels in ASD individuals with the pervasive behavior and disruption of social behavior observed in patients. We hypothesize that these differences could be due to an increased TGF-β1 expression in ASD individuals already present during development, which could lead to opposite long-term effects of this cytokine on these behaviors.