New treatments have to be developed for posttraumatic stress disorder (PTSD) patients that do not respond to current therapies. Gene expression studies such as microarrays could identify genes that could be targeted for the development of new PTSD treatments. Pavlovian fear conditioning in rodents experimentally mimics PTSD and fear extinction mimics exposure therapy used to treat PTSD. Since the infralimbic cortex (IL) is critical for the recall of fear extinction in rodents, I used microarray technology to identify gene expression changes in IL after extinction as a means to identify novel molecules critical for fear extinction-induced plasticity. Interestingly, ephrin type-B receptor 2 (EphB2), a tyrosine kinase receptor recently associated with Alzheimer's disease and anxiety, was down-regulated in IL five hours after fear extinction. Based on these findings, I hypothesize that signaling via EphB2 in IL plays an important role in consolidating the fear extinction memory. To test this hypothesis I designed three specific aims.
In Aim 1, I will determine the effects of fear extinction on EphB2 mRNA, protein expression, protein cleavage, and protein tyrosine phosphorylation in IL.
In Aim 2, a plasmid containing EphB2-shRNA will be infused into IL prior and after fear extinction to test whether inhibiting EphB2 signaling can facilitate extinction.
In Aim 3, I will test the role of the cleavage/activation of EphB2 by matrix metalleproteinase 9 (MMP-9) in IL in fear extinction and determine whether MMP-9 inhibitors can facilitate fear extinction. The findings of this proposal will determine if EphB2 plays a prominent role in the consolidation of fear extinction memory and whether EphB2 can be considered a novel target for the development of drugs to enhance exposure therapy and the treatment of PTSD patients.
PTSD affects some people exposed to traumatic events, making them unable to have a productive normal life. The current extinction-based exposure therapy is not effective in all PTSD patients. To enhance exposure therapy and relieve the symptoms of PTSD patients, new molecular targets have to be identified to allow the design of drugs that are specific for enhancing exposure therapy. This proposal identifies EphB2 as a new molecular target for enhancing fear extinction and potentially exposure therapy.