Neural Plasticity / 2016 / Article / Fig 1

Review Article

Linking Mitochondria to Synapses: New Insights for Stress-Related Neuropsychiatric Disorders

Figure 1

The mitochondria-synapse signaling loop is modulated by glucocorticoids. Acute and moderate glucocorticoid peaks rapidly promote the formation of new dendritic spines via a membrane GR coupled to the activation of the LIMK1-cofilin pathway. In contrast, glucocorticoid-mediated spine elimination is delayed and requires the transcription of new gene products. GR is present at pre- and postsynaptic membranes, in the cytoplasm, the nucleus, and the mitochondria. The exact mechanisms and series of molecular events are unknown. Trains of electrical stimulation impose an intense energy demand that can result in mitochondrial fragmentation if unmet, thereby increasing the ATP : AMP ratio, the activation of the AMP-sensing kinase to signal the local decrease of energy stores. New mitochondria can be captured in a calcium-dependent manner where energy stores are low. The levels of intracellular calcium determine whether or not to activate the calcium-dependent phosphatase calcineurin, which can be disruptive for the focal adhesion of mitochondria by dephosphorylating cofilin, impacting on the polymerization of the acting cytoskeleton tethering membranes to the mitochondria. Additionally, synaptic pruning can result from NMDAR-dependent LTD, calcium-dependent cytochrome c release whose end product is the activated caspase-3. Caspase-3 exerts local nonapoptotic effects via a broad spectrum of synaptic substrates. To this end, caspase-3 activity is retained at hotspots thanks to transcription of inhibitors of apoptosis proteins (IAP), some of which are GR-regulated genes, and by a constitutive active ubiquitin-proteasome degradation system from which caspase-3 can only be protected within the hotspots. Select transcriptional targets of GR have been involved in the regulation of respiration, mitochondrial uncoupling, and elongation, the dynamics of the actin cytoskeleton and synaptic plasticity.

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