Activation of a novel α _2A AR‐spinophilin‐cofilin axis determines the effect of α ₂ adrenergic drugs on fear memory reconsolidation

Posttraumatic stress disorder (PTSD) after the pandemic has emerged as a major neuropsychiatric component of the post-acute COVID-19 syndrome, yet the current pharmacotherapy for PTSD is limited. The use of adrenergic drugs to treat PTSD has been suggested, yet hindered by conflicting clinical results and a lack of mechanistic understanding of drug actions. Our studies using both genetically modified mice and human induced pluripotent stem cell-derived neurons reveals a novel α2A adrenergic receptor (α2A AR)-spinophilin-cofilin axis in the hippocampus that is critical for regulation of contextual fear memory reconsolidation. We have further found that two a2 ligands, clonidine and guanfacine, exhibit differential abilities in activating this signaling axis to disrupt fear memory reconsolidation. Stimulation of a2A AR with clonidine, but not guanfacine, promotes the interaction of cofilin, an actin binding protein, with the dendritic spine scaffolding protein spinophilin to induce cofilin activation at the synapse. Spinophilin-dependent regulation of cofilin is required for clonidine-induced disruption of contextual fear memory reconsolidation. Our results inform the interpretation of differential clinical observations of these two drugs on PTSD, and suggest that clonidine could provide immediate treatment for PTSD symptoms related to the current pandemic. Furthermore, our study indicates modulation of dendritic spine morphology may represent an effective strategy for development of new pharmacotherapies for PTSD.