Chemogenetic activation of the medial prefrontal cortex alleviates the impaired extinction of fear memory through the increase in the binding of EGR1 and TET1 in an animal model of PTSD.

Rationale: Impaired extinction of fear memory (EFM) is one of the principal symptoms of posttraumatic stress disorder (PTSD). We recently reported that chemogenetic activation (CA) of the infralimbic cortex (ILC) during extinction training did not reduce fear instantly but rather facilitated later extinction retrieval in a single prolonged stress (SPS) rats, an animal model of PTSD.

Objective: We examined the mechanism by which CA alleviates the impaired EFM in SPS rats.

Methods: We measured protein levels of Early Growth Response 1 (EGR1) and ten-eleven translocation methylcytosine dioxygenase 1 (TET1) by western blotting, levels of binding of these two proteins by co-immunoprecipitation and western blotting, and levels of 5-hydroxymethylcytosine (5hmC), an indicator of DNA demethylation, by ELISA. Bobcat339 was used as a selective TET inhibitor, and EFM was evaluated using extinction training and extinction testing following contextual fear conditioning.

Results: CA of the ILC increased the binding of EGR1 and TET1 and increased the 5hmc level in the prefrontal cortex. Administration of Bobcat339 inhibited the 5hmc increase and the alleviation of impaired EFM by the CA of the ILC in SPS rats. The extinction training was indispensable for the increased binding of EGR1 and TET1 and the alleviation of impaired EFM in response to the CA of the ILC.

Conclusion: Our results suggest that CA alleviates the impaired EFM via the increase in EGR1-TET1 binding in SPS rats. Pharmacotherapy promoting DNA demethylation through the activation of the TET1 cascade may be pivotal in the treatment of PTSD.