2005 Progress Report: Environmental Factors in the Etiology of Autism; Animal Models of Autism

EPA Grant Number: R829388C005
Subproject: this is subproject number 005 , established and managed by the Center Director under grant R829388
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: CECEHDPR - University of California at Davis Center for the Study of Environmental Factors in the Etiology of Autism
Center Director: Pessah, Isaac N.
Title: Environmental Factors in the Etiology of Autism; Animal Models of Autism
Investigators: Amaral, David G. , Berman, Robert F.
Institution: University of California - Davis
EPA Project Officer: Saint, Chris
Project Period: September 30, 2001 through September 29, 2002
Project Period Covered by this Report: September 30, 2004 through September 29, 2005
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2001) RFA Text |  Recipients Lists
Research Category: Health , Children's Health , Health Effects

Objective:

To establish behavioral ethograms in mice and non-human primates to study the influence of environmental triggers that influence the development of social behaviors and co-morbidities associated with autism.

Progress Summary:

Project 2 has developed a comprehensive battery of behavioral tests that enable us to assess social interaction and social communication in mice following exposure to xenobiotics (e.g., organic mercury, PCB’s, PBDE’s, and vaccine antigens). We have continued to add new behavioral tests appropriate for characterizing development in mice, and to re-evaluate specific tests within the current battery to focus on those measures that provide useful and reliable information on mouse development and nervous system function after xenobiotic exposure. Projects 2 and 3 have been working very closely to integrate results from mouse behavior with molecular and cellular studies to understand mechanisms.

Maternal autoantibodies isolated from mothers of autistic children produce stereotypy and altered social behavior in a rhesus macaque model. We previously reported a unique pattern of autoantibodies directed at brain proteins occur in approximately 30% of women who gave birth to more than one autistic child. The IgG fraction from the sera of these women was purified and administered to rhesus macaques early during gestation and the behavioral outcomes in their offspring were then measured using an extensive behavioral ethogram. Monkeys from mothers receiving the autism autoantibody IgG (AA-IgG), but not control IgG, developed stereotypic behaviors by 8 months of age. The AA-IgG monkeys also showed significantly higher activity in the mother-preference task and during a stressful situation. We find this very intriguing in light of the increase in activity often exhibited by autistic children (Sturm et al. 2004). We will now proceed to adapt the AA-IgG monkey model to mice in an effort to develop the first autism-susceptibility model in a rodent species.

Homer 1 knockout mice have altered social behavior and aggression. In the current period Project 3 investigators published the discovery that Homer proteins, in addition to their known scaffolding functions that regulate synaptic plasticity within central neurons, also have a catalytic function toward micorsomal Ca2+ channels known as ryanodine receptors (RyRs; Feng et al. 2002, Ward et al. 2003). Homer association with RyRs enhances the gain of Ca2+ signaling events, and is likely to contribute to neuronal plasticity. The investigators have shown these very channels to be the target of non-coplanar PCBs (see below). Most recently we revised a manuscript for publication describing the use of our comprehensive behavioral testing battery to characterize Homer 1 knockout animals (Jaubert et al. 2005). These animals show highly unusual social interactions; with the knockouts demonstrating increased social interaction, whereas mice heterozygous for Homer 1 show greatly increased aggression.


Journal Articles on this Report : 3 Displayed | Download in RIS Format

Other subproject views: All 3 publications 3 publications in selected types All 3 journal articles
Other center views: All 145 publications 133 publications in selected types All 132 journal articles
Type Citation Sub Project Document Sources
Journal Article Burke K, Cheng Y, Li B, Petrov A, Joshi P, Berman RF, Reuhl KR, DiCicco-Bloom E. Methylmercury elicits rapid inhibition of cell proliferation in the developing brain and decreases cell cycle regulator, cyclin E. NeuroToxicology 2006;27(6):970-981. R829388 (2006)
R829388 (Final)
R829388C005 (2005)
R829391 (2006)
R833292 (2009)
R833292 (Final)
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  • Journal Article Greco CM, Berman RF, Martin RM, Tassone F, Schwartz PH, Chang A, Trapp BD, Iwahashi C, Brunberg J, Grigsby J, Hessl D, Becker EJ, Papazian J, Leehey MA, Hagerman RJ, Hagerman PJ. Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain 2006;129(1):243-255. R829388 (2006)
    R829388 (Final)
    R829388C005 (2005)
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  • Journal Article Jaubert PJ, Golub MS, Lo YY, Germann SL, Dehoff MH, Worley PF, Kang SH, Schwarz MK, Seeburg PH, Berman RF. Complex, multimodal behavioral profile of the Homer1 knockout mouse. Genes, Brain and Behavior 2007;6(2):141-154. R829388 (2006)
    R829388 (Final)
    R829388C005 (2005)
    R833292 (2007)
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  • Supplemental Keywords:

    animal models, mice, non-human primates, neurobehavioral toxicology, autoantibodies, mercury, PCBs, PBDEs, social behavior,, RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, ENVIRONMENTAL MANAGEMENT, Toxicology, Health Risk Assessment, Chemistry, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, Disease & Cumulative Effects, Physical Processes, Children's Health, genetic susceptability, Biology, Risk Assessment, chemical exposure, neurotoxic, xenobiotics, biomarkers, neurodevelopment, gene-environment interaction, pesticides, exposure, halogenated aromatics, children, neurobehavioral, neurodevelopmental, neurotoxicity, etiology, susceptibility, neurobehavioral effects, autism, biological markers, mechanisms, exposure assessment, neurological development, biomarker, synergistic interactions

    Progress and Final Reports:

    Original Abstract
    2002 Progress Report
    2003 Progress Report


    Main Center Abstract and Reports:

    R829388    CECEHDPR - University of California at Davis Center for the Study of Environmental Factors in the Etiology of Autism

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R829388C001 Environmental Factors in the Etiology of Autism; Analytic Biomakers (xenobiotic) Core
    R829388C002 Environmental Factors in the Etiology of Autism; Cell Activation/Signaling Core
    R829388C003 Environmental Factors in the Etiology of Autism; Molecular Biomakers Core
    R829388C004 Environmental Factors in the Etiology of Autism; Childhood Autism Risks from Genetics and the Environment (The CHARGE Study)
    R829388C005 Environmental Factors in the Etiology of Autism; Animal Models of Autism
    R829388C006 Environmental Factors in the Etiology of Autism; Molecular and Cellular Mechanisms of Autism