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

Abstract

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.

Clonidine for post-traumatic stress disorder: a systematic review of the current evidence

“…In that context, clonidine's ability to reduce nightmares and improve sleep may be related to a desensitization of the noradrenergic system via alpha-2 receptor agonism (Southwick et al, 1999 ). In addition, clonidine showed a dose-dependent effect on REM and non-REM sleep (Miyazaki et al, 2004 ), which has been related to improved memory consolidation (Lebow & Chen, 2016 ; Marin et al, 2020 ; Saggu et al, 2023 ; Schulz et al, 2002 ). However, further studies on the specific pathways through which clonidine acts are warranted (Marin et al, 2020 ; Schulz et al, 2002 ).…”

“…Previous trials of prazosin have demonstrated higher effectiveness when used in conjunction with psychotherapy (Raskind et al, 2013 ), and a similar debate pertains to the use of psychedelics [specifically concerning the use of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy] in PTSD (Feduccia & Mithoefer, 2018 ; Smith et al, 2022 ). This suggests that future research could investigate the potential benefits of combining clonidine with PTSD-specific psychotherapies such as eye movement desensitization and reprocessing (EMDR) (Cuijpers et al, 2020 ), also bearing in mind preliminary evidence of the impact of clonidine in memory consolidation (Groch et al, 2011 ; Saggu et al, 2023 ).…”

“…Clonidine inhibits the release of noradrenaline in the locus coeruleus and has shown promising results in case reports, retrospective chart reviews, and pilot studies for treating sleep disorders and overall symptoms in PTSD patients (Alao et al, 2012 ; Bange & Melvin, 2022 ; Burek et al, 2021 ; Kinzie et al, 1994 ). Recent studies suggest that clonidine may also restore rapid eye movement (REM) sleep and have an impact on emotional memory consolidation (Jang et al, 2022 ; Miyazaki et al, 2004 ; Saggu et al, 2023 ), but good-quality research and solid evidence are lacking with respect to the effectiveness and tolerability of clonidine in PTSD. Although clonidine has been registered for medical use for several decades, it is not yet approved for treating PTSD-related symptoms.…”

AGS3-based optogenetic GDI induces GPCR-independent Gβγ signaling and macrophage migration

“…G protein-coupled receptors (GPCRs) represent ∼5% of the human genome, have immense pathophysiological significance, and thus a primary target for drug discovery (1)(2)(3)(4). GPCRs constitute one of the largest and most diverse superfamilies of cell surface receptors that sense a wide array of extracellular ligands, ranging from photons to small molecules and peptides (5).…”