Dataset Information

Quantitative Proteomics Combined Independent PRM Analysis Reveals the Mitochondrial and Synaptic Mechanism Underlying Norisoboldine’s Antidepressant Effects

ABSTRACT: Major depressive disorder (MDD) is a common disease affecting 300 million people worldwide. The existing drugs are ineffective for approximately 30% of patients, so it is urgent to develop new antidepressant drugs with novel mechanisms. Here, we found that norisoboldine (NOR) showed an antidepressant efficacy in the chronic social defeat stress (CSDS) depression model in the tail suspension, forced swimming, and sucrose consumption tests. We then utilized the drug-treated CSDS mice paradigm to segregate and gain differential protein cohorts of CSDS versus CON(CSDSCON), imipramine (IMI)-treated versus CSDS (IMICSDS), and NOR-treated versus CSDS (NORCSDS) from the prefrontal cortex. These protein expression alterations were first analyzed by ANOVA with p<0.05. The protein cluster 1, in which the pattern of protein levels similar to the mood pattern, showed enrichment in functions and localizations related to mitochondrion and synapses. Further GO analysis of the common proteins for NORCSDS-IMICSDS groups and NORCSDS-CSDSCON groups supported the findings from ANOVA analysis. We employed Protein-Protein interaction (PPI) analysis to examine the shared protein cohorts of NORCSDS-IMICSDS and NORCSDS-CSDSCON, revealing an enrichment of the proteins associated with the mitochondrial and synaptic functions. Further independent analysis using parallel reaction monitoring (PRM) revealed that several proteins related to mitochodrial function, including Cox7c, Mrp142, Naa30, Ighm, Ssu72, Mrps30, Apoh, Acbd5, and Cdv3, exhibited regulation in the NOR-treated group. Additionally, proteins associated with synaptic function, such as Dcx, Arid1b, Rnf112, Apoa4 and Fam3c, were also observed to undergo modulation in the NOR-treated groups. These findings suggest that the proteins involved in depression treatment exert differential effects the mitochondrial and synaptic regulation of the mice prefrontal proteome. In summary, the current proteomic research conducted on the prefrontal cortex has provided valuable insights into the specific and shared molecular mechanisms underlying pathophysiology and treatment to CSDS-induced depression, shedding light on the therapeutic effects of Norisoboldine.

INSTRUMENT(S): autoflex

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: 磊李

LAB HEAD: Jing Du

PROVIDER: PXD047064 | Pride | 2025-05-06

REPOSITORIES: Pride

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Quantitative proteomics combined independent PRM analysis reveals the mitochondrial and synaptic mechanism underlying norisoboldine's antidepressant effects.

Li Lei L Kan Weijing W Zhang Yi Y Wang Tianyi T Yang Feng F Ji Tengfei T Wang Gang G Du Jing J

Translational psychiatry 20241002 1

Major depressive disorder (MDD) is a common disease affecting 300 million people worldwide. The existing drugs are ineffective for approximately 30% of patients, so it is urgent to develop new antidepressant drugs with novel mechanisms. Here, we found that norisoboldine (NOR) showed an antidepressant efficacy in the chronic social defeat stress (CSDS) depression model in the tail suspension, forced swimming, and sucrose consumption tests. We then utilized the drug-treated CSDS mice paradigm to s ...[more]

PMID: 39358323

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Project description:Background: Examining transcriptional regulation by existing antidepressants in key neural circuits implicated in depression, and understanding the relationship to transcriptional mechanisms of susceptibility and natural resilience, may help in the search for new therapeutics. Further, given the heterogeneity of treatment response in human populations, examining both treatment response and non-response is critical. Methods: We compared the effects of a conventional monoamine-based tricyclic antidepressant, imipramine (14 daily injections), and a rapidly acting, experimental, non-monoamine-based antidepressant, ketamine (single injection), in mice subjected to chronic social defeat stress, a validated model of depression, and used RNA-sequencing to analyze transcriptional profiles associated with susceptibility, resilience and antidepressant response and non-response in prefrontal cortex (PFC), nucleus accumbens, hippocampus, and amygdala. Results: We identified approximately equal numbers of responder and non-responder mice following ketamine or imipramine treatment. Ketamine induced more expression changes in hippocampus than other brain regions; imipramine induced more expression changes in nucleus accumbens and amygdala. Transcriptional profiles in ketamine and imipramine responders were most similar in PFC, where the least transcriptional regulation occurred for each drug. Non-response reflected both the lack of response-associated gene expression changes and unique gene regulation. In responders, both drugs reversed susceptible associated transcriptional changes as well as induced resilient associated transcription in PFC, with effects varying by drug and brain region studied. Conclusions: We generated a uniquely large resource of gene expression data in four inter-connected limbic brain regions implicated in depression and its treatment with imipramine or ketamine. Our analyses highlight the PFC as a key site of common transcriptional regulation by both antidepressant drugs and in both reversing susceptibility and inducing resilience associated molecular adaptations. In addition, we found region-specific effects of each drug suggesting both common and unique effects of imipramine versus ketamine. mRNA profiles of susceptibility to chronic social defeat stress as well as treatment response were generated across 4 separate brain regions, with a sample size of 3-5 per group.

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