Mitochondrial reactive oxygen species regulate the strength of inhibitory GABA-mediated synaptic transmission

Abstract

Neuronal communication imposes a heavy metabolic burden in maintaining ionic gradients essential for action potential firing and synaptic signaling. Although cellular metabolism is known to regulate excitatory neurotransmission, it is still unclear whether the brain’s energy supply affects inhibitory signaling. Here we show that mitochondrial-derived reactive oxygen species (mROS) regulate the strength of postsynaptic GABAA receptors at inhibitory synapses of cerebellar stellate cells. Inhibition is strengthened through a mechanism that selectively recruits α3-containing GABAA receptors into synapses with no discernible effect on resident α1-containing receptors. Since mROS promotes the emergence of postsynaptic events with unique kinetic properties, we conclude that newly-recruited α3-containing GABAA receptors are activated by neurotransmitter released onto discrete postsynaptic sites. Although traditionally associated with oxidative stress in neurodegenerative disease, our data identifies mROS as a putative homeostatic signaling molecule coupling cellular metabolism to the strength of inhibitory transmission.

Proteomic pathway analysis of the hippocampus in schizophrenia and bipolar affective disorder implicates 14-3-3 signaling, aryl hydrocarbon receptor signaling, and glucose metabolism: Potential roles in GABAergic interneuron pathology

“…In our analyses, antioxidant enzymes such as superoxide dismutase 1 (SOD1), were found altered in hippocampal tissue (Focking et al, 2011b) ( Table 1 and 4) and were central to the top IPA protein networks in schizophrenia and bipolar disorder (Figures 1 and 2), supporting previous findings Coughlin et al, 2013;Emiliani et al, 2014). Increased brain levels of ROS lead to selective damage of fast-spiking GABAergic interneurons in rodent cortex (Behrens et al, 2007), and can directly regulate the strength of inhibitory GABAergic transmission at postsynaptic site through GABAA receptor recruitment (Accardi et al, 2014). Based on these findings, one can speculate that the effects of novel therapies for psychotic disorders involving anti-diabetic and antioxidant strategies (Dean et al, 2012;McIntyre et al, 2012;Reddy and Reddy, 2011) could partly be mediated via protection of hippocampal GABAergic interneuron function.…”

Mitochondrial dynamics in neuronal injury, development and plasticity

“…During synaptic transmission, the mitochondrial ATP generation produces ROS, which can regulate the strength of synaptic transmission. Specifically, it was shown that mitochondria-derived ROS selectively recruit α3 subunit-containing GABA A receptors to inhibitory synapses in order to increase the frequency and amplitude of inhibitory postsynaptic currents (IPSCs) in cerebellar stellate neurons (Accardi et al, 2014). Future studies are required to determine how mitochondrial dynamics impact on ROS-mediated regulation of synaptic transmission.…”

“…However, this is an oversimplification of mitochondrial physiology. In addition to carrying out ATP synthesis through oxidative phosphorylation, mitochondria are also important for Ca 2+ signaling (Brini et al, 2014;Nicholls, 2005;Duchen, 2000;Clapham, 2007), cell death (Tait and Green, 2013;Duchen, 2000), steroid synthesis (Miller, 2011), reactive oxygen species (ROS) production and sequestration (Zorov et al, 2014;Hamanaka and Chandel, 2010;Shadel and Horvath, 2015;Accardi et al, 2014), and neurotransmitter synthesis and inactivation (Rowley et al, 2012;Bak et al, 2005;Waagepetersen et al, 2000). 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.…”

6-Containing GABAA Receptors Are the Principal Mediators of Inhibitory Synapse Strengthening by Insulin in Cerebellar Granule Cells

“…However, recent work from our laboratory has revealed that mitochondrial-derived reactive oxygen species (mROS) strengthen inhibitory synapses of cerebellar stellate cells by a mechanism distinct in two important ways. First, synapse strengthening is mediated by the recruitment of ␣3-containing receptors and not resident ␣1-receptors (Accardi et al, 2014). Second, ␣3-receptors are targeted to functionally separate postsynaptic sites from ␣1-receptors (Accardi et al, 2014), implying that not all synapses are strengthened by mROS.…”

“…First, synapse strengthening is mediated by the recruitment of ␣3-containing receptors and not resident ␣1-receptors (Accardi et al, 2014). Second, ␣3-receptors are targeted to functionally separate postsynaptic sites from ␣1-receptors (Accardi et al, 2014), implying that not all synapses are strengthened by mROS. Whether this novel mechanism is unique to stellate cells or more commonly used throughout the CNS remains to be investigated.…”