GSK3ß, a centre-staged kinase in neuropsychiatric disorders, modulates long term memory by inhibitory phosphorylation at Serine-9

Accumulating evidence implicates deregulation of GSK3ß 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 GSK3ß in learning and memory remains to be explored in depth. We here report increased phosphorylation of GSK3ß 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 GSK3ß[S9A] show impaired memory in these tasks. Furthermore, GSK3ß[S9A] mice displayed impaired hippocampal L-LTP and facilitated LTD. Application of actinomycin, but not anisomycin, mimicked GSK3ß[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 GSK3ß 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 GSK3ß signaling, including AD, bipolar disorder and schizophrenia.