Glycogen synthase kinase-3β (GSK-3β) is an enzyme that adds phosphate groups to the protein tau. This phosphorylated tau aggregates in the brain during Alzheimer’s disease, and seems to be involved in the memory dysfunction that characterizes this disorder.
Drugs that block GSK-3β may therefore prevent or slow the progression of Alzheimer’s disease. However, a group at the RIKEN Brain Science Institute in Wako led by Akihiko Takashima has shown that blocking GSK-3β could actually induce memory problems. These findings are reported in the journal PLoS ONE1.
The researchers created mice that lacked one of two gene copies of GSK-3β, and exposed the mice to various memory exams. First, in the ‘Morris Water Maze’ test, the mice were trained to locate a hidden platform in a pool of water. After the first few days of training, all the mice learned the location of the hidden platform equally well. But with additional days of training, the mice lacking one copy of the GSK-3β gene seemed to forget the platform location. This may represent ‘retrograde amnesia’—or impairment to long-term memory formation.
New memories are easily forgotten, but can start to become stabilized in the brain through a process called consolidation, and become permanently fixed in the brain through reconsolidation.
To determine which of these processes is defective in mice lacking one copy of the GSK-3β gene, Takashima and colleagues examined the mice in a test known as contextual fear conditioning. The mice were initially exposed to a light shock in the foot in a novel environment. To examine consolidation, the researchers then re-exposed the mice to the novel environment a week later. To examine reconsolidation, they exposed the mice to the novel environment again both a day and a week later. For both tests, the researchers observed how well the mice seemed to remember that the novel environment was linked to the foot shock.
Based on these tests, Takashima and colleagues concluded that mice lacking one copy of the GSK-3β gene had normal consolidation but defective reconsolidation (Fig. 1). The same was true when normal mice were given a drug that blocks GSK-3β.
Takashima thinks the findings may help us understand memory dysfunction during aging. “When elderly people are confronted with a new idea, they recall related memories to help them understand this new information,” he says. “The frequent need to recall and reconsolidate memories relies on the activation of GSK-3β, which leads to tau phosphorylation and aggregation.”
Kimura, T., Yamashita, S., Nakao, S., Park, J.-M., Murayama, M., Mizoroki, T., Yoshiike, Y., Sahoara, N. & Takashima, A.GSK-3β is required for memory reconsolidation in adult brain. PLoS ONE 3, e3540 (2008).
The corresponding author for this highlight is based at the RIKEN Laboratory for Alzheimer’s Disease