GSK3β, a centre-staged kinase in neuropsychiatric disorders, modulates long term memory by inhibitory phosphorylation at Serine-9

Accumulating evidence implicates deregulation of GSK3 beta as a converging pathological event in Alzheimer's disease and in neuropsychiatric disorders, including bipolar disorder and schizophrenia. Although these neurological disorders share cognitive dysfunction as a hallmark, the role of GSK3 beta in learning and memory remains to be explored in depth. We here report increased phosphorylation of GSK3 beta at Serine-9 following cognitive training in two different hippocampus dependent cognitive tasks, i.e. inhibitory avoidance and novel object recognition task. Conversely, transgenic mice expressing the phosphorylation defective mutant GSK3 beta[S9A] show impaired memory in these tasks. Furthermore, GSK3 beta[S9A] mice displayed impaired hippocampal L-LTP and facilitated LTD. Application of actinomycin, but not anisomycin, mimicked GSK3 beta[S9A] induced defects in L-LTP, suggesting that transcriptional activation is affected. This was further supported by decreased expression of the immediate early gene c-Fos, a target gene of CREB. The combined data demonstrate a role for GSK3 beta in long term memory formation, by inhibitory phosphorylation at Serine-9. The findings are fundamentally important and relevant in the search for therapeutic strategies in neurological disorders associated with cognitive impairment and deregulated GSK3 beta signaling, including AD, bipolar disorder and schizophrenia. (C) 2009 Elsevier Inc. All rights reserved.