Activation of a novel α2AAR-spinophilin-cofilin axis determines the effect of α2 adrenergic drugs on fear memory reconsolidation

Posttraumatic stress disorder (PTSD) after the pandemic has emerged as a major neuropsychiatric component of post-acute COVID-19 syndrome, yet the current pharmacotherapy for PTSD is limited. The use of adrenergic drugs to treat PTSD has been suggested; however, it is hindered by conflicting clinica...

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Published in:Molecular psychiatry 2023-02, Vol.28 (2), p.588-600
Main Authors: Saggu, Shalini, Chen, Yunjia, Cottingham, Christopher, Rehman, Hasibur, Wang, Hongxia, Zhang, Sixue, Augelli-Szafran, Corinne, Lu, Sumin, Lambert, Nevin, Jiao, Kai, Lu, Xin-Yun, Wang, Qin
Format: Article
Language:English
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Actin
Adrenergic receptors
Behavioral Sciences
Biological Psychology
Clonidine
Cofilin
COVID-19
Dendritic spines
Drug therapy
Fear
Medicine
Medicine & Public Health
Mental disorders
Neurosciences
Pandemics
Pharmacotherapy
Pluripotency
Post traumatic stress disorder
Psychiatry
Spinophilin
Stem cells
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Summary:Posttraumatic stress disorder (PTSD) after the pandemic has emerged as a major neuropsychiatric component of post-acute COVID-19 syndrome, yet the current pharmacotherapy for PTSD is limited. The use of adrenergic drugs to treat PTSD has been suggested; however, it is 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, reveal a novel α 2A adrenergic receptor (α 2A AR)-spinophilin-cofilin axis in the hippocampus that is critical for regulation of contextual fear memory reconsolidation. In addition, we have found that two α 2 ligands, clonidine and guanfacine, exhibit differential abilities in activating this signaling axis to disrupt fear memory reconsolidation. Stimulation of α 2A AR with clonidine, but not guanfacine, promotes the interaction of the actin binding protein cofilin with the receptor and 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 that modulation of dendritic spine morphology may represent an effective strategy for the development of new pharmacotherapies for PTSD.
ISSN:1359-4184
1476-5578
DOI:10.1038/s41380-022-01851-w