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

Abstract

Traumatic brain injury (TBI) has many long-term consequences, including impairment in memory and changes in mood. Glycogen synthase kinase 3β (GSK-3β) in its phosphorylated form (p-GSK-3β) is considered to be a major contributor to memory problems that occur post-TBI. We have developed an antisense that targets the GSK-3β (GAO) gene. Using a model of closed-head concussive TBI, we subjected mice to TBI and injected GAO or a random antisense (RAO) 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 GAO show improved memory in both object recognition and T-maze compared with RAO- treated mice that were subjected to TBI. Next, we verified that GAO blocked the surge in phosphorylated GSK-3β post-TBI. Mice were subjected to TBI and injected with antisense 15 min post-TBI with GAO or RAO. Mice were euthanized at 4 and 72 h post-TBI. Analysis of p-ser9GSK-3β, p-tyr216GSK-3β, and phospho-tau (p-tau)404 showed that mice that received a TBI+RAO had significantly higher p-ser9GSK-3β, p-tyr216GSK-3β, and p-tau404 levels than the mice that received TBI+GAO and the Sham+RAO mice. The current finding suggests that inhibiting GSK-3β increase after TBI with an antisense directed at GSK-3β prevents learning and memory impairments.