A Brain Signaling Framework for Stress-Induced Depression and Ketamine Treatment Elucidated by Phosphoproteomics

Abstract

Depression is a common affective disorder characterized by significant and persistent low mood. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, is reported to have a rapid and durable antidepressant effect, but the mechanisms are unclear. Protein phosphorylation is a post-translational modification that plays a crucial role in cell signaling. Thus, we present a phosphoproteomics approach to investigate the mechanisms underlying stress-induced depression and the rapid antidepressant effect of ketamine in mice. We analyzed the phosphoprotein changes induced by chronic unpredictable mild stress (CUMS) and ketamine treatment in two known mood control centers, the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). We initially obtained >8,000 phosphorylation sites. Quantitation revealed 3,988 sites from the mPFC and 3,196 sites from the NAc. Further analysis revealed that changes in synaptic transmission-related signaling are a common feature. Notably, CUMS-induced changes were reversed by ketamine treatment, as shown by the analysis of commonly altered sites. Ketamine also induced specific changes, such as alterations in synapse organization, synaptic transmission, and enzyme binding. Collectively, our findings establish a signaling framework for stress-induced depression and the rapid antidepressant effect of ketamine.

Phosphoproteomics implicates glutamatergic and dopaminergic signalling in the antidepressant-like properties of the iron chelator deferiprone

“…Its relevance for depression research is due to the fact that dysregulation of the phosphoproteome is observed in MDD patients, as well as other CNS disorders (Martins- de-Souza et al, 2012;Morshed et al, 2021). Furthermore, phosphoproteomics analysis has been utilised to determine the acute molecular mechanism of action of antidepressant drugs such as ketamine (Xiao et al, 2020).…”

“…Inc, LA Jolla, USA). Size of treatment group numbers were based on prior studies (n=4-6) for a total of 21 samples (Mees, Li, et al, 2022; Mees, Tran, et al, 2022; Xiao et al, 2020).…”

Crosstalk among Calcium ATPases: PMCA, SERCA and SPCA in Mental Diseases

“…Moreover, the basal and CaM-stimulated PMCA activities were reduced in the synaptosomal membranes mainly due to a direct interaction of the drug within large catalytic loop and competing with CaM for binding in the C-terminal domain of the pump [ 87 , 88 ]. Similarly, emerging studies also suggest the interaction of ketamine with CaM-dependent enzymes, in particular CaMKII [ 89 , 90 ], but no specific functional studies largely limit the conclusions on CaM and PMCA-mediated Ca 2+ regulation in schizophrenia.…”

MiR-139-5p has an antidepressant-like effect by targeting phosphodiesterase 4D to activate the cAMP/PKA/CREB signaling pathway

“…Environmental challenges or stressful events, such as chronic ultra-mild stress (CUMS), alter microRNAs (miRNAs) in the brain, including the hippocampus (9,10). MiRNAs are a class of small, noncoding RNAs able to mediate cleavage or translational repression of target mRNAs by binding preferentially to 3' untranslated regions (UTRs) (11).…”