Individuals with Down syndrome are impaired in specific learning and memory tasks and display early onset cognitive decline. Similar deficits have been described in the Ts65Dn mouse model of Down syndrome. Calcineurin is a calcium/calmodulin-dependent protein phosphatase that mediates many cellular processes, including synaptic plasticity. The investigator hypothesizes that abnormalities in calcineurin signaling are relevant to the cognitive impairments seen in Down syndrome and mouse models because (i) learning and memory deficits similar to those observed in individuals with Down syndrome and Ts65Dn mice can be caused by calcineurin signaling defects, and (ii) the chromosome 21 Down Syndrome Critical Region 1 (DSCR1) genes, superoxide dismutase (SOD1), a-amyloid precursor protein (APP), and Purkinjie cell protein 4 (PCP4) each directly or indirectly inhibits calcineurin activity. Importantly, calcineurin activity is decreased in Down syndrome brains, and preliminary data show it is also decreased in brains of Ts65Dn mice. The investigator suggests that understanding gene/phenotype correlations in Down syndrome will best be achieved by focusing experiments on a pathway relevant to cognitive function and predicted to be perturbed by overexpression of chromosome 21 genes. To validate this approach for the calcineurin pathway, she proposes the following specific aims: (1) measure levels and localization of calcineurin activity in brain regions of adolescent, young adult, and aged Ts65Dn mice; (2) evaluate the consequences of abnormalities found in Aim 1 by measuring phosphorylation levels of calcineurin targets, endocytic protein dynamin, apoptosis protein BAD, amyloid plaque component tau, transcription factors Elk, NFATc4, and CREB, and calcineurin inhibitor DSCR1; and (3) dissect the contribution to the calcineurin-related abnormalities of the genomic region containing SOD1 and APP by repeating Aims 1 and 2 in the Ts1Cje mouse model of Down syndrome that is trisomic for only DSCR1 and PCP4 of the four candidate genes. We propose this work as an RO3 to establish her expertise in this area, to describe the extent of calcineurin abnormalities in the segmental trisomy mouse models, and to generate data to justify long-term, more detailed investigations of the contribution of this pathway to cognition. Results from this pilot project will direct future studies of the underlying genetic mechanism, as well as behavioral and cognitive consequences of abnormalities in this pathway.

R03HD049460

2005-04-01

2008-03-31