Neuroanatomic and behavioral traits for autistic disorders in age-specific restricted index selection mice.

The pathogenesis of neurodevelopmental disorders such as autism is believed to be influenced by interactions between genetic and environmental factors, and appropriate animal models are needed to assess the influence of such factors on relevant neurodevelopmental phenotypes. A set of inbred mouse strains (Atchley strains) including A12 (E+L0) and A22 (E-L0) were generated by age-specific restricted index selection from a baseline random-bred ICR mouse population obtained from Harlan Sprague-Dawley [Atchley et al. (1997) Genetics 146(2):629-640; Indianapolis, IN, USA). As compared with the A22 strain, A12 mice had significantly increased early (P0-P10) body weight gain with minimal changes in late (P28-P56) body weight gain. We found that these strains also differed in brain weight, brain volume, cell proliferation, and FGF-2 levels in certain brain regions. Specifically, brain weight and volume were significantly greater in A12 mice than that in A22 mice at P10 and P28. Quantitative analysis of bromodeoxyuridine (BrdU) labeling of proliferating cells showed that the number of BrdU-positive cells in the A12 strain were significantly greater in the frontal cortex and lesser in the dentate gyrus than that in the A22 strain at P28. Western blot revealed that fibroblast growth factors-2 (FGF-2), but not brain-derived neurotrophic factor (BDNF), expression was significantly increased in the frontal cortex of A12 strain at P28. Also, A12 mice exhibited decreased intra-strain social interaction and increased repetitive stereotyped behaviors at P28. Our study suggests that A12 mice may partially mimic the anatomic and behavioral traits of patients with neurodevelopmental disorders such as autism spectrum disorders, and therefore may yield insights into the developmental mechanisms involved in their pathogenesis.

Corticosterone and related receptor expression are associated with increased beta-amyloid plaques in isolated Tg2576 mice.

Previously, we reported that the stress associated with chronic isolation was associated with increased beta-amyloid (Abeta) plaque deposition and memory deficits in the Tg2576 transgenic animal model of Alzheimer's disease (AD) [Dong H, Goico B, Martin M, Csernansky CA, Bertchume A, Csernansky JG (2004) Effects of isolation stress on hippocampal neurogenesis, memory, and amyloid plaque deposition in APP (Tg2576) mutant mice. Neuroscience 127:601-609]. In this study, we investigated the potential mechanisms of stress-accelerated Abeta plaque deposition in this Tg2576 mice by examining the relationship between plasma corticosterone levels, expression of glucocorticoid receptor (GR) and corticotropin-releasing factor receptor-1 (CRFR1) in the brain, brain tissue Abeta levels and Abeta plaque deposition during isolation or group housing from weaning (i.e. 3 weeks of age) until 27 weeks of age. We found that isolation housing significantly increased plasma corticosterone levels as compared with group-housing in both Tg+ mice (which contain and overexpress human amyloid precursor protein (hAPP) gene) and Tg- mice (which do not contain hAPP gene as control). Also, isolated, but not group-housed animals showed increases in the expression of GR in the cortex. Furthermore, the expression of CRFR1 was increased in isolated Tg+ mice, but decreased in isolated Tg- mice in both cortex and hippocampus. Changes in the components of hypothalamic-pituitary-adrenal (HPA) axis were accompanied by increases in brain tissue Abeta levels and Abeta plaque deposition in the hippocampus and overlying cortex in isolated Tg+ mice. These results suggest that isolation stress increases corticosterone levels and GR and CRFR1 expression in conjunction with increases in brain tissue Abeta levels and Abeta plaque deposition in the Tg2576 mouse model of AD.