Cannabinoid Receptor Agonist Affects Murine Contextual Fear Conditioned Memory after Mild Traumatic Brain Injury

Abstract

Mild traumatic brain injuries are common and can lead to memory deficits, partly due to hippocampal dysfunction. Mild traumatic brain injury causes a decrease in network excitability in area CA1 of the hippocampus. We have previously demonstrated that applying the cannabinoid receptor agonist WIN55,212-2 to injured brain slices, restores action potential firing to levels not significantly different than action potentials recorded in slices from uninjured (sham) animals. Here, we evaluated whether WIN55,212-2 also improves hippocampal-dependent memory in vivo using a contextual fear conditioning paradigm. Mice subjected to lateral fluid percussion injury were treated with WIN55,212-2 at doses of 0.75, 0.25, or 0.1mg/kg. Memory is thought to consist of three components: encoding (conditioning), consolidation, and retrieval (testing). At 0.75mg/kg and 0.25mg/kg, all mice froze significantly more than control mice indicating that mouse locomotion was affected at those doses. At concentrations of 0.1mg/kg we observed that injured and sham mice showed no significant differences in freezing rate compared to control sham mice but froze significantly more than injured controls. When administered at 0.1mg/kg only on conditioning days, we saw a similar effect as when injected on both conditioning and testing days. These results suggest that WIN55,212-2 at 0.1 mg/kg primarily aids memory encoding rather than retrieval. Overall, the study demonstrates that at the 0.1mg/kg dose, WIN55,212-2 can restore hippocampal-dependent memory function in lateral fluid percussion injury mice, providing insights into the potential therapeutic role of cannabinoid receptor agonists in mitigating memory deficits following mild traumatic brain injury.