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

Abstract

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.

Keywords

• GSK3ß
• Alzheimer's disease
• Neuropsychiatric disorders
• Cognition
• Synaptic plasticity
• Long term potentiation