SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE

For Project 1, we plan to block excessive NMDAR activation based on a novel family of NMDAR subunits, the NR3 family. We are developing ligand-binding domain (LBD)-derived screening assays to screen ligands selective for the NR3 subunit of the NMDAR. These ligands will be further characterized and refined by secondary assays, chemical modification, and cocrystallization. For Project 2, we will use cells derived from Down syndrome (DS) patients. The goal will be to show that the excessive endogenous A? from DS-derived cells can produce synaptic damage. We plan to restore synaptic vs. extrasynaptic ‘balance’ in the hippocampal autapse in vitro model using the novel NMDAR antagonist NitroMemantine vs. Memantine in order to prevent ?-amyloid (A?)—mediated neuronal damage. For these experiments, we will use induced pluripotent stem cell (iPSC)-derived and fetal brain-derived neurons from Down syndrome (DS) patients. In the ‘bridge-year’ funded by this ARRA grant, we will first characterize the DS iPSC-derived neurons and compare to fetal brain-derived cortical neurons obtained from legal DS therapeutic abortions. For Project 3, we plan to characterize the Ts65Dn mouse model of Down syndrome (DS) by (i) determining if APP/A? produced in the Ts65Dn results in increased extrasynaptic glutamate compared to wild-type (WT) littermate mice, and (ii) determining the levels of NR3A subunit and takusan in the Ts65Dn mouse brain. The current ARRA funding will allow us to test if these transgenic mice manifest abnormal extracellular glutamate levels, in the brain parenchyma by microdialysis and monitor levels of the NR3A subunit of the NMDA receptor and the associated protein, takusan, in the DS model mouse brain vs. wild-type littermates. The ARRA funding for the Core will provide for continuation of program coordination and supply of cell culture services and mice and frogs necessary for execution of the various projects.

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