Involvement of PGC-1α in the formation and maintenance of neuronal dendritic spines

The formation, maintenance and reorganization of synapses are critical for brain development and the responses of neuronal circuits to environmental challenges. Here we describe a novel role for peroxisome proliferator-activated receptor gamma co-activator 1 alpha, a master regulator of mitochondrial biogenesis, in the formation and maintenance of dendritic spines in hippocampal neurons. In cultured hippocampal neurons, proliferator-activated receptor gamma coactivator 1 alpha overexpression increases dendritic spines and enhances the molecular differentiation of synapses, whereas knockdown of proliferator-activated receptor gamma coactivator 1 alpha inhibits spinogenesis and synaptogenesis. Proliferator-activated receptor gamma co-activator 1 alpha knockdown also reduces the density of dendritic spines in hippocampal dentate granule neurons in vivo. We further show that brain-derived neurotrophic factor stimulates proliferator-activated receptor gamma co-activator-1 alpha-dependent mitochondrial biogenesis by activating extracellular signal-regulated kinases and cyclic AMP response element-binding protein. Proliferator-activated receptor gamma co-activator-1 alpha knockdown inhibits brain-derived neurotrophic factor-induced dendritic spine formation without affecting expression and activation of the brain-derived neurotrophic factor receptor tyrosine receptor kinase B. Our findings suggest that proliferator-activated receptor gamma co-activator-1 alpha and mitochondrial biogenesis have important roles in the formation and maintenance of hippocampal dendritic spines and synapses.