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

Attempts have been made to use glycogen synthase kinase-3 beta (GSK3 beta) inhibitors for prophylactic treatment of neurocognitive conditions. However the use of lithium, a nonspecific inhibitor of GSK3 beta results in mild cognitive impairment in humans. The effects of global GSK3 beta inhibition or knockout on learning and memory in healthy adult mice are also inconclusive. Our study aims to better understand the role of GSK3 beta in learning and memory through a more regionally, targeted approach, specifically performing lentiviral-mediated knockdown of GSK3 beta within the dentate gyrus (DG). DG-GSK3 beta-silenced mice showed impaired contextual fear memory retrieval. However, cue fear memory, spatial memory, locomotor activity and anxiety levels were similar to control. These GSK3 beta-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 GSK3 beta in the DG provides better understanding on the role of GSK3 beta in learning and memory.