Inhibition of Glycogen Synthase Kinase 3 beta as a Treatment for the Prevention of Cognitive Deficits after a Traumatic Brain Injury

摘要

Traumatic brain injury (TBI) has many long-term consequences, including impairment in memory and changes in mood. Glycogen synthase kinase 3 beta (GSK-3 beta) in its phosphorylated form (p-GSK-3 beta) is considered to be a major contributor to memory problems that occur post-TBI. We have developed an antisense that targets the GSK-3 beta ((G)AO) gene. Using a model of closed-head concussive TBI, we subjected mice to TBI and injected (G)AO or a random antisense ((R)AO) 15 min post-injury. One week post-injury, mice were tested in object recognition with 24 h delay. At 4 weeks post- injury, mice were tested with a T-maze foot shock avoidance memory test and a second object recognition test with 24 h delay using different objects. Mice that received (G)AO show improved memory in both object recognition and T-maze compared with (R)AO- treated mice that were subjected to TBI. Next, we verified that (G)AO blocked the surge in phosphorylated GSK-3 beta post-TBI. Mice were subjected to TBI and injected with antisense 15 min post-TBI with (G)AO or (R)AO. Mice were euthanized at 4 and 72 h post-TBI. Analysis of p-ser9GSK-3 beta, p-tyr216GSK-3 beta, and phospho-tau (p-tau)(404) showed that mice that received a TBI+(R)AO had significantly higher p-ser9GSK-3 beta, p-tyr216GSK-3 beta, and p-tau(404) levels than the mice that received TBI+(G)AO and the Sham+(R)AO mice. The current finding suggests that inhibiting GSK-3 beta increase after TBI with an antisense directed at GSK-3 beta prevents learning and memory impairments.