We have generated a monoclonal antibody, B6B21, and have shown that it significantly enhances acquisition rates in hippocampus-dependent trace eyeblink conditioning in rabbits, halving the number of trials required to reach 80% conditioned responses. Previous studies, with a variety of model systems, have shown that B6B21 acts as a partial ago mst at the glycine site of the N-methyl-D-aspartate receptor (NMDAR). NMDAR play a central role in learning, memory loss due to aging and Alzheimer's disease, modulation of pain perception, and possibly schizophrenia. Glutamate excitotoxicity, mediated by overactive NMDAR, is one of the principal ways that neurons are damaged by stroke. The long-term goal of Neurotherapeutics, Inc. is to develop a memory enhancer by using B6B21 as a template to create peptides and/or mimetics that will be more efficacious than the original antibody, and cross the blood-brain barrier. This will be accomplished by cloning and sequencing the variable heavy region of B6B21. This Phase I application proposes to test B6B21 in aged rabbits using the hippocampus-dependent, trace conditioning paradigm. We must establish concentration-dependence and efficacy in memory-impaired mammals (rabbits) before we can segue into structure-function studies with modified antibody
