Drug development targeting the glycogen synthase kinase-3beta (GSK-3beta)-mediated signal transduction pathway: role of GSK-3beta in adult brain.

Glycogen synthase kinase-3beta (GSK-3beta) is a constitutively active kinase. Since its activation results in neurofibrillary tangle (NFT) deposits in aged and Alzheimer's disease (AD) brains, GSK-3beta may be inhibited under normal conditions but activated under pathological conditions. Given its link to NFT formation, we sought to determine whether GSK-3beta exists in the brain as a "pathological time bomb" that promotes disease development. To address this hypothesis, we analyzed GSK-3beta heterozygote (GSK+/-) mice, which express GSK-3beta at 50% wild-type levels. When tested in the Morris water maze test, GSK+/- mice surprisingly exhibited retrograde amnesia. Further analysis indicated that GSK+/- mice had impaired memory reconsolidation but normal memory consolidation. Therefore, we concluded that GSK-3beta activation is required for memory reconsolidation in the adult brain.