Whether it’s the sure thing you bet on for the Super Bowl or the grant that keeps escaping your grasp, some memories are best forgotten. However, memories are complicated to say the least, and with most of us left wanting to retain a few of the more enjoyable examples, a targeted editing approach would certainly help. Thankfully, new research from the lab of Elizabeth Heller at the University of Pennsylvania (USA) has continued their investigation of cyclin-dependent kinase 5 (Cdk5), a key player in fear memory and stress behavior, where they establish that targeted epigenetic editing can wipe fear memory in female, but not male, mice.
Previously, the talented team of epigenetic editors demonstrated that they could attenuate the depressive phenotype from male social defeat stress by targeting histone acetylation to activate Cdk5 in the reward center of the mouse brain, the nucleus accumbens. In their latest study, the group utilized virally-mediated gene transfer of an engineered zinc finger protein (ZFP) to target Cdk5 in the hippocampus, which represents the learning and memory center of the mouse brain. The p65 effector domain of their Cdk5-ZFP-p65 construct deposits histone H3 lysine 9/14 acetylation (H3K9/14ac) on the Cdk5 promoter, thus activating gene expression. The authors then subjected these mice and their wild-type counterparts to behavioral (fear conditioning) and molecular assays (RT-qPCR, ChIP-qPCR, and Western blots).
Here’s what the mouse memories turned up:
- In wild-type mice, males display a stronger long-term fear memory retrieval than females, suggesting that females possess a distinct fear memory protection mechanism
- However, they didn’t observe any differences in short-term fear memory retrieval between sexes
- The sexually dimorphic wild-type behavior upon long-term fear memory retrieval associates with sex-specific activation of Cdk5 in males, where increased H3K9/14ac of the Cdk5 promoter drives mRNA and protein expression
- While utilizing Cdk5-ZFP-p65 to understand the causal relevance of the male-specific profile, the team surprisingly discovered that the targeted epigenetic editing attenuates short and long-term fear memory retrieval in female, but not male, mice
- This difference between the sexes leads to female-specific hyperphosphorylation of Tau, a downstream target of Cdk5 involved in learning and memory
Senior author Elizabeth Heller shares, “We examined both sexes, and found male-specific epigenetic activation of Cdk5 expression after fear conditioning, a model of traumatic memory. Remarkably, [epigenetic] manipulation reduced fear memory retrieval and increased Tau phosphorylation in female, but not male mice. Taken together, epigenetic editing uncovered a female-specific role of Cdk5 activation in repressing fear-induced memory.”
The team also offers a hypothetical model to explain the observed sexual dimorphism. In females, blocking fear memory-based activation of Cdk5 controls differing downstream effects, such as Tau hyperphosphorylation. Overall, these findings provide novel insights into sexual dimorphism and post-traumatic stress disorder.
Catch all the epigenetically edited mouse memories in Biological Psychiatry, January 2019