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

Abstract

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 (PGC-1α), a master regulator of mitochondrial biogenesis, in the formation and maintenance of dendritic spines in hippocampal neurons. In cultured hippocampal neurons, PGC-1α overexpression increases dendritic spines and enhances the molecular differentiation of synapses, whereas knockdown of PGC-1α inhibits spinogenesis and synaptogenesis.. PGC-1α knockdown also reduces the density of dendritic spines in hippocampal dentate granule neurons in vivo. We further show that brain-derived neurotrophic factor (BDNF) stimulates PGC-1α-dependent mitochondrial biogenesis by activating ERKs and CREB. PGC-1α knockdown inhibits BDNF to promote dendritic spine formation without affecting expression and activation of the BDNF receptor TrkB. Our findings suggest that PGC-1α and mitochondrial biogenesis play important roles in the formation and maintenance of hippocampal dendritic spines and synapses.

AMPK agonist AICAR improves cognition and motor coordination in young and aged mice

“…In muscles, the increase in energy metabolism is evidenced by the up-regulation of genes directly involved in mitochondrial electron transport chain: complex I (NDUFA5, NDUFB9, NDUFB4) and complex IV, and also an up-regulation of complex II (SDHD); moreover, also Krebs Cycle is enhanced, both by complex II itself and by the AcCoA indirectly produced by the overexpression of DLD (Harris et al 1997). AICAR enhanced expression of mitochondria related genes in the hippocampus, consistent with a role of energy metabolism related factors such as PGC1a in synaptic plasticity (Cheng et al 2012); however, the main increase in gene expression in the hippocampus was for neural plasticity related genes such as ATXN10, RTN4, and YWHAG.…”

Mitochondrial dynamics in neuronal injury, development and plasticity

“…Mitochondrial biogenesis serves to increase mitochondrial mass, which is a necessary checkpoint for initiating neuronal differentiation and development (Agostini et al, 2016). Moreover, the stimulation of dendritic spine development by brainderived neurotrophic factor (BDNF) is, at least partly, dependent upon peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A, hereafter referred to as PGC1-α), a master transcriptional regulator of mitochondrial biogenesis (Cheng et al, 2012). Accordingly, knockdown of PGC1-α inhibits, whereas overexpression of PGC1-α increases mitochondrial biogenesis and dendritic spine formation (Cheng et al, 2012).…”

“…Given the importance of processes, such as ATP production, Ca 2+ transients, neurotransmitter metabolism and ROS signaling, in synaptic transmission it is not surprising that recent work has illustrated that perturbations in mitochondrial physiology exert profound effects on neuronal development and function. Mitochondrial ATP production, Ca 2+ buffering, neurotransmitter metabolism and ROS signaling themselves are spatially and temporally regulated in neurons through mitochondrial localization (Brodin et al, 1999;Jayashankar and Rafelski, 2014;Li et al, 2004;Niescier et al, 2013;Rueda et al, 2014;Sheng, 2014;Vos et al, 2010), mitochondrial bioenergetics (Rueda et al, 2014;Dickey and Strack, 2011), and mitochondrial biogenesis (Cheng et al, 2012), all of which are strongly influenced by mitochondrial dynamics, which entails mitochondrial fission, fusion and transport.…”

Challenging Oneself Intermittently to Improve Health

“…Numerous studies have shown that BDNF can protect neurons against degeneration and death in experimental models relevant to the pathogenesis of Alzheimer's, Parkinson's and Huntington's diseases (Duan et al, 2003;Zuccato and Cattaneo, 2009;Intlekofer and Cotman, 2013). Exercise and BDNF signaling bolster the stress resistance of neurons in multiple ways including by enhancing DNA repair (Yang et al, 2014), stimulating mitochondrial biogenesis (Cheng et al, 2012), inducing the expression of 'anti-apoptotic' proteins such as Bcl-2 and Bcl-xL (Allsopp et al, 1995;Chao et al, 2011), and upregulating expression of antioxidant enzymes (Mattson et al, 1995;Marosi et al, 2012). Even in aged mice, running can upregulate the expression of genes involved in synaptic plasticity and cellular bioenergetics, while downregulating genes associated with oxidative stress (Stranahan et al, 2010).…”