The role of hippocampal CaMKII in resilience to trauma-related psychopathology

Abstract

Traumatic stress exposure can form persistent trauma-related memories. However, only a minority of individuals develop post-traumatic stress disorder (PTSD) symptoms upon exposure. We employed a rat model of PTSD, which enables differentiating between exposed-affected and exposed-unaffected individuals. Two weeks after the end of exposure, animals were tested behaviorally, following an exposure to a trauma reminder, identifying them as trauma affected or unaffected. In light of the established role of hippocampal synaptic plasticity in stress and the essential role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in hippocampal based synaptic plasticity, in two separate experiments, we pharmacologically inhibited CaMKII or knocked-down CaMKII in the dorsal dentate gyrus of the hippocampus (dDG) following exposure to the same trauma paradigm. Both manipulations brought down the prevalence of affected individuals in the trauma- exposed population. A day after the last behavioral test, long-term potentiation (LTP) was examined in the dDG as a measure of synaptic plasticity. Trauma exposure reduced the ability to induce LTP, whereas, contrary to expectation, CaMKII-kd reversed this effect. Further examination revealed that reducing CaMKII expression, enables the formation of CaMKII-independent LTP, which may enable increased resilience in the face of a traumatic experience. The current findings further emphasize the pivotal role dDG has in stress resilience.