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Increase in Cerebellar Neurotrophin-3 and Oxidative Stress Markers in Autism

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Abstract

Autism is a neurodevelopmental disorder characterized by social and language deficits, ritualistic–repetitive behaviors and disturbance in motor functions. Data of imaging, head circumference studies, and Purkinje cell analysis suggest impaired brain growth and development. Both genetic predisposition and environmental triggers have been implicated in the etiology of autism, but the underlying cause remains unknown. Recently, we have reported an increase in 3-nitrotyrosine (3-NT), a marker of oxidative stress damage to proteins in autistic cerebella. In the present study, we further explored oxidative damage in the autistic cerebellum by measuring 8-hydroxydeoxyguanosine (8-OH-dG), a marker of DNA modification, in a subset of cases analyzed for 3-NT. We also explored the hypothesis that oxidative damage in autism is associated with altered expression of brain neurotrophins critical for normal brain growth and differentiation. The content of 8-OH-dG in cerebellar DNA isolated by the proteinase K method was measured using an enzyme-linked immunosorbent assay (ELISA); neurotrophin-3 (NT-3) levels in cerebellar homogenates were measured using NT-3 ELISA. Cerebellar 8-OH-dG showed trend towards higher levels with the increase of 63.4% observed in autism. Analysis of cerebellar NT-3 showed a significant (p = 0.034) increase (40.3%) in autism. Furthermore, there was a significant positive correlation between cerebellar NT-3 and 3-NT (r = 0.83; p = 0.0408). These data provide the first quantitative measure of brain NT-3 and show its increase in the autistic brain. Altered levels of brain NT-3 are likely to contribute to autistic pathology not only by affecting brain axonal targeting and synapse formation but also by further exacerbating oxidative stress and possibly contributing to Purkinje cell abnormalities.

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Acknowledgments

We thank the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland for providing us with human postmortem brain specimens. We thank the Autism Research Institute and the Japanese Society for Promotion of Science for their support of this study.

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Authors and Affiliations

  1. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    Elizabeth M. Sajdel-Sulkowska

  2. Department of Psychiatry, Brigham and Women’s Hospital, BLI-151, 221 Longwood Ave., Boston, MA, 02115, USA

    Elizabeth M. Sajdel-Sulkowska

  3. Department of Integrative Physiology, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan

    Ming Xu & Noriyuki Koibuchi

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  1. Elizabeth M. Sajdel-Sulkowska
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Correspondence to Elizabeth M. Sajdel-Sulkowska.

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Sajdel-Sulkowska, E.M., Xu, M. & Koibuchi, N. Increase in Cerebellar Neurotrophin-3 and Oxidative Stress Markers in Autism. Cerebellum 8, 366–372 (2009). https://doi.org/10.1007/s12311-009-0105-9

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