Deficits in performance of hippocampal-based tasks and loss of cholinergic markers in the medial septal neurons (MSN) in the basal forebrain that supply cholinergic input to the hippocampus are seen in individuals with Down syndrome and in the Ts65Dn mouse model of Down syndrome. We hypothesize that abnormalities in the MAP Kinase signaling pathway are relevant to the deficits and to the loss of neuronal markers. This hypothesis is supported by observations that the concentration and distribution of nerve growth factor (NGF) is altered in the hippocampus and the medial septal cholinergic neurons of the Ts65Dn mice, that NGF functions through endocytosis and MAPK signaling, that hippocampal deficits can be caused by MAPK signaling defects, and that the chromosome 21 genes Intersectin 1 (ITSN1), synaptojanin 1 (SYNJ1), transient lymphoma and metastasis 1 (TIAM1), dual specificity kinase 1A (DYRK1A), and beta-amyloid precursor protein (APP) interact with and/or directly affect components of endocytosis, MAPK signaling pathways or downstream gene transcription. Importantly, our preliminary data show abnormalities of the MAPK pathway in Ts65Dn mice. Substantial gains in understanding this complex system can best be achieved by focusing experiments on a pathway relevant to cognitive function. To do this, we propose the following specific aims: (1) to assess MAPK activity in the hippocampus of Ts65Dn mice by measuring levels of phosphorylated protein or kinase activity of pathway endpoints Erk1, Erk2, Erk5 and Jnk; (2) to evaluate [he source of abnormalities found in aim (1) by measuring activation levels of upstream MAPK components dynamin, Ras, Rac and Akt, each of which is affected by one or more of the chromosome 21 proteins; and (3) measuring levels of activation of MAPK targets, Creb, Sos and CHAT. Fulfillment of these aims will define the direction and magnitude of abnormalities in a pathway known to be relevant to hippocampal-based learning. We propose this work as an RO3 to establish our expertise in this area and to describe the extent of MAP Kinase pathway abnormalities in the Ts65Dn mouse. Results from this pilot project will direct future studies of the underlying genetic mechanisms, possibilities for pharmacological manipulation, and behavioral and cognitive consequences of abnormalities in this pathway.
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