This proposal aims to genetically determine the involvement of excess N-methyl-D-aspartate receptor (NMDAR) activity in the pathogenesis of early cognitive deficits of Down syndrome. Oligomeric Ap peptides are known to be generated very early in Down syndrome because of the extra copy of the APP (amyloid precursor protein) gene on chromosome 21 (the trisomic chromosome in humans with Down syndrome). We propose that the early synaptic damage that is known to occur in Down syndrome brains may, at least in part, be due to excessive levels of Ap peptides. One possible mechanism by which excessive AB may cause synaptic loss and neuronal injury is via NMDAR activation, since it is known that AB increases glutamate release from astrocytes. NR3A subunits inhibit NMDAR activity and act as neuroprotective molecules that mitigate neuronal injury caused by various experimental paradigms. Our recent data indicate that AB induces greater synaptic injury to NR3A-knockout (KO) neurons compared to wild-type (WT) neurons. In addition, we have identified a large gene family that we named takusan (meaning many in Japanese), which regulates synaptic activity. Based on the properties of takusan proteins, we postulated that this molecule might also protect synapses. In this proposal, we will genetically cross Ts65Dn mice, a mouse model of Down syndrome, with mice mutant in NR3A or takusan genes. We will then evaluate the consequences of these crosses for early neurological and cognitive deficits, as well as dendritic spine loss and electrophysiological abnormalities that have been observed in Ts65Dn mice. These experiments will determine whether NR3A and/or takusan play mechanistic roles in possible protection from the synaptic damage that occurs in Down syndrome. Our Specific Aims are as follows: (1) To determine the potential ill effect of NRSA KO of the NMDAR in the pathogenesis of cognitive deficits in Down syndrome. (2) To determine the potential beneficial effect of expression of the NR3A subunit of the NMDAR on the pathogenesis of cognitive deficits in Down syndrome. (3) To identify the effect of takusan in protecting from AB-induced synaptic spine loss.