Laura Toso

Altered expression of KIF17, a kinesin motor protein associated with NR2B trafficking, may mediate learning deficits in a Down syndrome mouse model

OBJECTIVE Down syndrome (DS), a major cause of mental retardation, affects 1 of 800 newborns. Mouse models for Down syndrome have been studied and found to have developmental and learning deficits, including the Ts65Dn (DS) mouse model. N-methyl-D-aspartate receptor NR2B subunit enhances synaptic plasticity. The up-regulation of KIF17, a motor protein that transports NR2B to the synaptic region parallels up-regulation of synaptic NR2B. Down regulation of KIF17 reflects up-regulation of less plastic NR2A subunit. We evaluated NR2B, NR2A, and KIF17 in Ts65Dn and control mice. STUDY DESIGN Ts65Dn (4) and control (4) adult brains were collected; NR2A, NR2B, and KIF17 were measured by Western blot and quantified using National Institutes of Health Image software. Comparisons were made using analysis of variance, < .05 was considered significant. RESULTS There was a significant decrease in KIF17 (P = .04) level in Ts65Dn mice as compared with the control animals, but there were no significant differences in the levels of NR2A (P = .79) and NR2B (P = .96). CONCLUSION The significant decrease of KIF17 inTs65Dn animals may in part mediate cognitive defects in DS.

Alterations in phosphorylated cyclic adenosine monophosphate response element of binding protein activity: a pathway for fetal alcohol syndrome-related neurotoxicity.

OBJECTIVE Fetal alcohol syndrome (FAS) is the leading cause of a spectrum of preventable nongenetic learning and behavioral disorders. In adult (FAS) mice, we measured phosphorylated cyclic adenosine monophosphate response element of binding protein (pCREB) staining in hippocampal subregions to evaluate a possible mechanism underlying FAS learning deficits. STUDY DESIGN Pregnant C57BL6/J mice were treated on gestational day 8 with alcohol or control (saline). After learning assessment, the offspring were perfused for immunohistochemistry and brain sections probed using SER 133 pCREB antibody. Relative staining density was assessed using National Institutes of Health Image software. Statistical analysis included analysis of variance with P < .05 considered significant. RESULTS In all hippocampal subregions, pCREB staining was greater in the control animals than in the alcohol-treated group (P < or = .0001). CONCLUSION In utero alcohol exposure decreased pCREB activity in hippocampal subregions of adult mice. The dentate gyrus had the most robust cumulative decrease in pCREB staining, suggesting FAS adult learning deficits may correlate to enhanced dentate gyrus neurodegeneration.