Identification of the embryonic stage when injury can cause autism has led to the insight that the disorder has initiated by changes in the developing brain stem. The shortening of the hindbrain and loss of cranial nerve neurons in an animal model of the insult and a human case of autism resemble features of the Hoxa-1 transgenic knockout mouse. Thus, it is now possible to suggest a unifying hypothesis regarding the multiple etiologies of autism: We propose that teratogens and genetic defects lead to similar developmental changes in the brain stem because mutations of early developmental genes are the cause of familial cases and the teratogens which cause the disease act by interfering with function of the same genes. The new finding that tone of the candidate genes is abnormal in some cases of autism supports this hypothesis. Using mice transgenic for the reporter lac Z, which have been created to signal the level of expression of Hoxa-1, we shall compare the effects of valproic acid (a known cause of autism) and 2-ethyhexanoic acid (a teratogen with similar somatic effects) to the effects of retinoic acid (a teratogen known to interfere with the Hox gene cascade, and now suspected to be cause of autism) on Hox gene expression. In addition, we shall compare the expression of markers on the rhombomeres in embryos from the same litters, using in situ hybridization. In older embryos we shall compare the effects of the three teratogens on the morphology of the developing brain stem, using immunocytochemistry and of traditional serial sectioning with cresyl violet staining to examining the early structure of the cranial nerves, ganglia, and nuclei. We shall mutation mutations of early developmental genes identified in Project III to create a house model of genetically- induced autism, and examined the morphology of the brain stem in transgenic mutants. Subjecting heterozygotes of the genetic model to teratogens will tell us whether teratologic injury can interact with genetic abnormality to alter the brain stem. The animal models developed in this project will be evaluated behaviorally in Project II. The studies of Project I will help us predict which teratogens are likely causes of autism, and further our understanding of the developmental origin of the brain abnormalities associated with the disorder.

Project Start
1999-06-01
Project End
2000-05-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Rochester
Department
Type
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Jablonski, Sarah A; Watson, Deborah J; Stanton, Mark E (2010) Role of medial prefrontal NMDA receptors in spatial delayed alternation in 19-, 26-, and 33-day-old rats. Dev Psychobiol 52:583-91
Murawski, Nathen J; Brown, Kevin L; Stanton, Mark E (2009) Interstimulus interval (ISI) discrimination of the conditioned eyeblink response in a rodent model of autism. Behav Brain Res 196:297-303
Watson, Deborah J; Herbert, Mariel R; Stanton, Mark E (2009) NMDA receptor involvement in spatial delayed alternation in developing rats. Behav Neurosci 123:44-53
Watson, Deborah J; Stanton, Mark E (2009) Spatial discrimination reversal learning in weanling rats is impaired by striatal administration of an NMDA-receptor antagonist. Learn Mem 16:564-72
Burman, M A; Murawski, N J; Schiffino, F L et al. (2009) Factors governing single-trial contextual fear conditioning in the weanling rat. Behav Neurosci 123:1148-52
Watson, Deborah J; Stanton, Mark E (2009) Medial prefrontal administration of MK-801 impairs T-maze discrimination reversal learning in weanling rats. Behav Brain Res 205:57-66
Watson, Deborah J; Stanton, Mark E (2009) Intrahippocampal administration of an NMDA-receptor antagonist impairs spatial discrimination reversal learning in weanling rats. Neurobiol Learn Mem 92:89-98
Levy, Susan E; Hyman, Susan L (2008) Complementary and alternative medicine treatments for children with autism spectrum disorders. Child Adolesc Psychiatr Clin N Am 17:803-20, ix
Stanton, Mark E; Peloso, Elizabeth; Brown, Kevin L et al. (2007) Discrimination learning and reversal of the conditioned eyeblink reflex in a rodent model of autism. Behav Brain Res 176:133-40
Stodgell, Christopher J; Ingram, Jennifer L; O'Bara, Melanie et al. (2006) Induction of the homeotic gene Hoxa1 through valproic acid's teratogenic mechanism of action. Neurotoxicol Teratol 28:617-24

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