Lentiviral silencing of GSK-3ß in adult dentate gyrus impairs contextual fear memory and synaptic plasticity.

ABSTRACT

Attempts have been made to use glycogen synthase kinase-3 beta (GSK3ß) inhibitors for prophylactic treatment of neurocognitive conditions. However the use of lithium, a non-specific inhibitor of GSK3ß results in mild cognitive impairment in humans. The effects of global GSK3ß inhibition or knockout on learning and memory in healthy adult mice are also inconclusive. Our study aims to better understand the role of GSK3ß in learning and memory through a more regionally, targeted approach, specifically performing lentiviral-mediated knockdown of GSK3ß within the dentate gyrus (DG). DG-GSK3ß-silenced mice showed impaired contextual fear memory retrieval. However, cue fear memory, spatial memory, locomotor activity and anxiety levels were similar to control. These GSK3ß-silenced mice also showed increased induction and maintenance of DG long-term potentiation (DG-LTP) compared to control animals. Thus, this region-specific, targeted knockdown of GSK3ß in the DG provides better understanding on the role of GSK3ß in learning and memory.