Synapse Pruning: Mitochondrial ROS with Their Hands on the Shears

Abstract

No overarching hypotheses tie the basic mechanisms of mitochondrial reactive oxygen species (ROS) production to activity dependent synapse pruning-a fundamental biological process in health and disease. Neuronal activity divergently regulates mitochondrial ROS: activity decreases whereas inactivity increases their production, respectively. Placing mitochondrial ROS as innate synaptic activity sentinels informs the novel hypothesis that: (1) at an inactive synapse, increased mitochondrial ROS production initiates intrinsic apoptosis dependent pruning; and (2) at an active synapse, decreased mitochondrial ROS production masks intrinsic apoptosis dependent pruning. Immature antioxidant defense may enable the developing brain to harness mitochondrial ROS to prune weak synapses. Beyond development, endogenous antioxidant defense constrains mitochondrial (ROS) to mask pruning. Unwanted age-related synapse loss may arise when mitochondrial ROS aberrantly recapitulate developmental pruning. Placing mitochondrial ROS with their hands on the shears is beneficial in early but deleterious in later life.

m.3243A > G-Induced Mitochondrial Dysfunction Impairs Human Neuronal Development and Reduces Neuronal Network Activity and Synchronicity

“…Local availability of mitochondrial mass is critical for generating and sustaining dendritic arbors, and disruption of mitochondrial distribution in mature neurons is associated with structural alterations in neurons (Kuzawa et al, 2014;Ló pez-Domé nech et al, 2016;Spillane et al, 2013). Loss of interneurons (Lax et al, 2016) and synapses and dendritic atrophy (in number and size) in specific brain areas, such as various cortical areas, the cerebellum, thalamus, and basal ganglia (Betts et al, 2006;Briston and Hicks, 2018;Chen et al, 2017;Cobley, 2018;Quintana et al, 2010;Turnbull et al, 2010) have also been reported in individuals with mitochondrial dysfunction. We found a reduced number of primary dendrites and dendritic nodes, decreased total and mean dendritic length, as well as a reduced surface covered by the dendritic network.…”

Mitochondrial dysfunction impairs human neuronal development and reduces neuronal network activity and synchronicity

“…The local availability of mitochondrial mass is critical for generating and sustaining dendritic arbors, and disruption of mitochondrial distribution in mature neurons is associated with structural alterations in the neurons (López-Doménech et al, 2016;Spillane et al, 2013;Kuzawa et al, 2014). Loss of interneurons , synapses and dendritic atrophy (both in number and size) in specific brain areas, such as various cortical areas, cerebellum, thalamus and basal ganglia (Cobley, 2018;Chen et al, 2017;Quintana et al, 2010;Betts et al, 2006;Turnbull et al, 2010;Briston and Hicks, 2018) have also been reported in individuals with mitochondrial dysfunction. We found a reduced number of primary dendrites and dendritic nodes, decreased total-and mean dendritic length, as well as reduced surface, covered by the dendritic network.…”

Deletion of the mitochondrial matrix protein cyclophilin-D prevents parvalbumin interneuron dysfunction and cognitive deficits in a mouse model of NMDA hypofunction

“…Taken together, our results underscore the impact of mitochondria on cortical networks and cognition. Mitochondria not only play essential roles in cell function, but their bioenergetics are crucial for proper neuronal development (Cobley, 2018), and even acute dysfunction impairs learning and memory (Mancini and Horvath, 2017). Here we illustrate how CypD activity can drive mitochondrial dysfunction in PVI and show that CypD may be a potential therapeutic target in protecting cognitive function in schizophrenia.…”