Knockdown of miRNA-134-5p rescues dendritic deficits by promoting AMPK-mediated mitophagy in a mouse model of depression.

Neuronal dendrites and dendritic spines are essential for normal synaptic transmission and may be critically involved in the pathophysiology of various neurological disorders, including depression. Emerging data supports the role of mitochondria in dendritic protrusions in modulating the development and morphological plasticity of spines. Mitophagy, a mitochondria-specific form of autophagy, is the fundamental process of clearing damaged mitochondria to maintain cellular homeostasis. As a brain-specific microRNA, miR-134 is localized to the synaptodendritic compartment of hippocampal neurons and negatively regulates the development of dendritic spines. However, the role of miR-134 in mitophagy related to dendritic deficits in the pathophysiology of depression remains unclear. In this study, we showed that miR-134-5p knockdown abrogated depressive-like behavioral symptoms and corrected aberrant spine morphology in hippocampal neurons of chronic unpredictable mild stress (CUMS) mice. Moreover, knockdown of miR-134-5p triggered autophagy in dendrites, improved mitochondrial impairment, and induced the generation of autophagosomes in the hippocampus of CUMS mice. We further found that AMP-activated protein kinase (AMPK), which mediates the impairment of defective mitochondria via mitophagy, can bind directly to miR-134-5p and is negatively regulated by this miRNA. This study demonstrates that miR-134-5p exerts an enormous effect on dendritic deficits by promoting AMPK-mediated mitophagy and provides a potential new target for antidepressant drug research and development.

• Publication year

  2022

• Venue

  Neuropharmacology

• Publication date

  2022-06-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.neuropharm.2022.109154PMID 35659969
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• R (-)-methoxetamine exerts rapid and sustained antidepressant effects and fewer behavioral side effects relative to S (+)-methoxetamine.

  2021cited by this paper
• Antidepressant-like effect of ginsenoside Rb1 on potentiating synaptic plasticity via the miR-134–mediated BDNF signaling pathway in a mouse model of chronic stress-induced depression

  2021cited by this paper
• Molecular mechanisms and physiological functions of mitophagy

  2021cited by this paper
• TM4SF5 Knockout Protects Mice From Diet-Induced Obesity Partly by Regulating Autophagy in Adipose Tissue

  2021cited by this paper
• Mitophagy in depression: pathophysiology and treatment targets.

  2021cited by this paper
• Hippocampal miR-211-5p regulates neurogenesis and depression-like behaviors in the rat.

  2021cited by this paper
• Molecular correlates of mitochondrial dysfunctions in major depression: evidence from clinical and rodent studies.

  2020cited by this paper
• AMPK activation induces mitophagy and promotes mitochondrial fission while activating TBK1 in a PINK1‐Parkin independent manner

  2020cited by this paper
• Calpain inhibition ameliorates depression-like behaviors by reducing inflammation and promoting synaptic protein expression in the hippocampus.

  2020cited by this paper
• Quercetin exerts antidepressant and cardioprotective effects in estrogen receptor α-deficient female mice via BDNF-AKT/ERK1/2 signaling.

  2020cited by this paper
• The Stage of the Estrus Cycle Is Critical for Interpretation of Female Mouse Social Interaction Behavior

  2020cited by this paper
• Inhibition of PINK1/Parkin-dependent mitophagy sensitizes multidrug-resistant cancer cells to B5G1, a new betulinic acid analog

  2019cited by this paper
• The protective effort of GPCR kinase 2–interacting protein‐1 in neurons via promoting Beclin1‐Parkin induced mitophagy at the early stage of spinal cord ischemia‐reperfusion injury

  2019cited by this paper
• Rb1, the Primary Active Ingredient in Panax ginseng C.A. Meyer, Exerts Antidepressant-Like Effects via the BDNF–Trkb–CREB Pathway

  2019cited by this paper
• Plasticity of dendritic spines: Molecular function and dysfunction in neurodevelopmental disorders

  2019cited by this paper
• The antidepressant effects of &agr;‐tocopherol are related to activation of autophagy via the AMPK/mTOR pathway

  2018cited by this paper
• Antidepressant Effects of Rhodomyrtone in Mice with Chronic Unpredictable Mild Stress-Induced Depression

  2018cited by this paper
• Activation of autophagy rescues synaptic and cognitive deficits in fragile X mice

  2018cited by this paper
• PINK1 and BECN1 relocalize at mitochondria-associated membranes during mitophagy and promote ER-mitochondria tethering and autophagosome formation

  2017cited by this paper
• AMPK: guardian of metabolism and mitochondrial homeostasis

  2017cited by this paper
• AMPK Promotes Autophagy by Facilitating Mitochondrial Fission.

  2016cited by this paper
• The ROCK Inhibitor Fasudil Prevents Chronic Restraint Stress-Induced Depressive-Like Behaviors and Dendritic Spine Loss in Rat Hippocampus

  2016cited by this paper
• Role of AMPK in regulation of LC3 lipidation as a marker of autophagy in skeletal muscle.

  2016cited by this paper
• Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants

  2016cited by this paper
• Location-dependent synaptic plasticity rules by dendritic spine cooperativity

  2016cited by this paper
• Dendritic Spines in Depression: What We Learned from Animal Models

  2016cited by this paper
• PINK1/Parkin-mediated mitophagy in mammalian cells.

  2015cited by this paper
• Mitochondria DNA Change and Oxidative Damage in Clinically Stable Patients with Major Depressive Disorder

  2015cited by this paper
• Activation of the AMPK-ULK1 pathway plays an important role in autophagy during prion infection

  2015cited by this paper
• Spine synapse remodeling in the pathophysiology and treatment of depression.

  2015cited by this paper
• Emerging role of synaptic actin-regulatory pathway in the pathophysiology of mood disorders

  2015cited by this paper
• Omega-3 polyunsaturated fatty acids and chronic stress-induced modulations of glutamatergic neurotransmission in the hippocampus.

  2014cited by this paper
• MiR‐134‐dependent regulation of Pumilio‐2 is necessary for homeostatic synaptic depression

  2014cited by this paper
• BECN1 is involved in the initiation of mitophagy

  2014cited by this paper
• Hippocampus atrophy and the longitudinal course of late-life depression.

  2014cited by this paper
• The role of autophagy in neurodegenerative disease

  2013cited by this paper
• ULK1 targets Beclin-1 in autophagy

  2013cited by this paper
• Depression, hippocampal volume changes, and cognitive decline in a clinical sample of older depressed outpatients and non-depressed controls

  2012cited by this paper
• Decreased Expression of Synapse-Related Genes and Loss of Synapses in Major Depressive Disorder

  2012cited by this paper
• MicroRNA networks direct neuronal development and plasticity

  2011cited by this paper
• Mitochondrial alterations and neuropsychiatric disorders.

  2011cited by this paper
• A novel pathway regulates memory and plasticity via SIRT1 and miR-134

  2010cited by this paper
• Activity-Dependent Dendritic Release of BDNF and Biological Consequences

  2009cited by this paper
• A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic spine morphogenesis

  2009cited by this paper
• Parkin is recruited selectively to impaired mitochondria and promotes their autophagy

  2008cited by this paper
• A Swedish national twin study of lifetime major depression.

  2006cited by this paper
• A brain-specific microRNA regulates dendritic spine development

  2006cited by this paper
• The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses.

  2004cited by this paper
• The functions of animal microRNAs

  2004cited by this paper
• Intensified Cloning Efforts Have Revealed Numer

  2004cited by this paper
• The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R).

  2003cited by this paper
• Dendritic spines: cellular specializations imparting both stability and flexibility to synaptic function.

  1994cited by this paper

• Circulating microRNAs as Biomarkers of Various Forms of Epilepsy

  2025cites this paper
• Mitochondrial dysfunction in depression: Mechanisms and targeted therapy strategies.

  2025cites this paper
• Impaired Synaptic Plasticity Mediated by Decreased GLUT1 in Hippocampal Astrocytes is Involved in Postoperative Cognitive Dysfunction in Elderly Mice

  2025cites this paper
• Hif-1α regulation of the Tet1-β-catenin-Dicer1-miRNAs pathway is involved in depression-like behavior in prenatal hypoxic male offspring.

  2025cites this paper
• Targeted miRNA Delivery in Epilepsy: Mechanisms, Advances, and Therapeutic Potential

  2025cites this paper
• Diagnostic value of serum miRNA-134-3p and miRNA-155-5p for monitoring seizure control in pediatric epilepsy.

  2025cites this paper
• Parkin, a Parkinson's disease-associated protein, mediates the mitophagy that plays a vital role in the pathophysiology of major depressive disorder.

  2024cites this paper
• Mitochondria in depression: The dysfunction of mitochondrial energy metabolism and quality control systems

  2024cites this paper
• Arjunolic acid ameliorates lipopolysaccharide-induced depressive behavior by inhibiting neuroinflammation via microglial SIRT1/AMPK/Notch1 signaling pathway.

  2024cites this paper
• Pharmacological mechanism of natural antidepressants: The role of mitochondrial quality control.

  2024cites this paper
• Blood‐derived microRNAs are related to cognitive domains in the general population

  2024cites this paper
• Deciphering the role of miRNA-134 in the pathophysiology of depression: A comprehensive review

  2024cites this paper
• MicroRNA-specific targets for neuronal plasticity, neurotransmitters, neurotrophic factors, and gut microbes in the pathogenesis and therapeutics of depression.

  2024cites this paper
• Combining Network Pharmacology and Transcriptomic Strategies to Explore the Pharmacological Mechanism of Total Ginsenoside Ginseng Root and Its Impact on Antidepressant Effects

  2024cites this paper
• Circulating miRNAs Associated With 3-Month Outcome in Patients With Acute Ischemic Stroke

  2024cites this paper
• Integrated analysis of microRNA and messenger RNA expression profiles reveals functional microRNA in infectious bovine rhinotracheitis virus-induced mitochondrial damage in Madin-Darby bovine kidney cells

  2024cites this paper
• Non-coding RNAs regulating mitochondrial function in cardiovascular diseases

  2023cites this paper
• Effectiveness of yoga for major depressive disorder: A systematic review and meta-analysis

  2023cites this paper
• Mitochondrial dysfunction: A fatal blow in depression.

  2023cites this paper
• Stress, microRNAs, and stress-related psychiatric disorders: an overview

  2023cites this paper
• Targeting mitophagy for depression amelioration: a novel therapeutic strategy

  2023cites this paper
• M1 macrophage-derived extracellular vesicle containing tsRNA-5006c promotes osteogenic differentiation of aortic valve interstitial cells through regulating mitophagy

  2022influential citation
• Baicalin ameliorates CUMS-induced depression-like behaviors through activating AMPK/PGC-1α pathway and enhancing NIX-mediated mitophagy in mice.

  2022cites this paper
• Fluoxetine Protects Against Inflammation and Promotes Autophagy in Mice Model of Post-traumatic Stress Disorder.

  2022cites this paper