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 depression-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. [Display omitted] • CUMS induced depression-like behavior is accompanied by hippocampal neuron damage and dendritic spine reduction. • Knockdown of miR-134-5p improved depression-like behavior and hippocampal dendritic spine morphology in CUMS mice. • Knockdown of miR-134-5p activated mitophagy in the hippocampal dendrites of CUMS mice. • Knockdown of miR-134-5p rescued hippocampal dendritic spine anomalies by targeting AMPK-mediated mitophagy. [ABSTRACT FROM AUTHOR]