Regulation of mitochondrial dynamics in astrocytes: Mechanisms, consequences, and unknowns

Jackson, Jordan E.; Robinson, Michael B.

doi:10.1002/glia.23252

Cited by 113 publications

(100 citation statements)

References 280 publications

(502 reference statements)

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“…This can develop from genetic defects in proteins such as PINK1 and Parkin, or through environmental factors that disrupt the mitochondrial electron transport chain (Lim, Ng, Grace, & Yao, 2012;Van Laar & Berman, 2013). Similarly, mitochondrial dynamics of glial cells can serve as an indicator of the inflammatory reactive state, including regulation of the astrocyte response to injury (Jackson & Robinson, 2017). Microglia treated with the purified endotoxin lipopolysaccharide (LPS) exhibit reduced basal and peak oxidative respiration rates (Orihuela, McPherson, & Harry, 2016).…”

Section: Discussionmentioning

confidence: 99%

Prokineticin‐2 promotes chemotaxis and alternative A2 reactivity of astrocytes

Neal

Luo

Harischandra

et al. 2018

Glia

103

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Astrocyte reactivity is disease- and stimulus-dependent, adopting either a pro-inflammatory A1 phenotype or a protective, anti-inflammatory A2 phenotype. Recently, we demonstrated, using cell culture, animal models and human brain samples, that dopaminergic neurons produce and secrete higher levels of the chemokine-like signaling protein Prokineticin-2 (PK2) as a compensatory protective response against neurotoxic stress. Since astrocytes express a high level of PK2 receptors, herein, we systematically characterize the role of PK2 in astrocyte structural and functional properties. PK2 treatment greatly induced astrocyte migration, which was accompanied by a shift in mitochondrial energy metabolism, a reduction in pro-inflammatory factors, and an increase in the anti-oxidant genes Arginase-1 and Nrf2. Overexpression of PK2 in primary astrocytes or in the in vivo mouse brain induced the A2 astrocytic phenotype with upregulation of key protective genes and A2 reactivity markers including Arginase-1 and Nrf2, PTX3, SPHK1 and TM4SF1. A small molecule PK2 agonist IS20 not only mimicked the protective effect of PK2 in primary cultures, but also increased glutamate uptake by upregulating GLAST. Notably, IS20 blocked not only MPTP-induced reductions in the A2 phenotypic markers SPHK1 and SCL10a6 but also elevation of the of A1 marker GBP2. Collectively, our results reveal that PK2 regulates a novel neuron-astrocyte signaling mechanism by promoting an alternative A2 protective phenotype in astrocytes, which could be exploited for development of novel therapeutic strategies for PD and other related chronic neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Prokineticin‐2 promotes chemotaxis and alternative A2 reactivity of astrocytes

Neal

Luo

Harischandra

et al. 2018

Glia

103

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“…Mitochondria in neurons and astrocytes generally exist in two pools, one of them stationary and the other one in motion (Misgeld & Schwarz, ). The latter pool apparently serves to enable a directed movement and arrest of mitochondria to sites of increased energy demand (Jackson & Robinson, ). Based on these findings, one could speculate that a repeated stimulation with glutamate will increase the number of mitochondria close to Na + (and Ca 2+ ) influx sites, thereby increasing the local capacity for rapid ATP production.…”

Section: Discussionmentioning

confidence: 99%

Relation between activity‐induced intracellular sodium transients and ATP dynamics in mouse hippocampal neurons

Gerkau

Lerchundi

Nelson

et al. 2019

The Journal of Physiology

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Key points Employing quantitative Na+‐imaging and Förster resonance energy transfer‐based imaging with ATeam1.03YEMK (ATeam), we studied the relation between activity‐induced Na+ influx and intracellular ATP in CA1 pyramidal neurons of the mouse hippocampus. Calibration of ATeam in situ enabled a quantitative estimate of changes in intracellular ATP concentrations. Different paradigms of stimulation that induced global Na+ influx into the entire neuron resulted in decreases in [ATP] in the range of 0.1–0.6 mm in somata and dendrites, while Na+ influx that was locally restricted to parts of dendrites did not evoke a detectable change in dendritic [ATP]. Our data suggest that global Na+ transients require global cellular activation of the Na+/K+‐ATPase resulting in a consumption of ATP that transiently overrides its production. For recovery from locally restricted Na+ influx, ATP production as well as fast intracellular diffusion of ATP and Na+ might prevent a local drop in [ATP]. Abstract Excitatory neuronal activity results in the influx of Na+ through voltage‐ and ligand‐gated channels. Recovery from accompanying increases in intracellular Na+ concentrations ([Na+]i) is mainly mediated by the Na+/K+‐ATPase (NKA) and is one of the major energy‐consuming processes in the brain. Here, we analysed the relation between different patterns of activity‐induced [Na+]i signalling and ATP in mouse hippocampal CA1 pyramidal neurons by Na+ imaging with sodium‐binding benzofurane isophthalate (SBFI) and employing the genetically encoded nanosensor ATeam1.03YEMK (ATeam). In situ calibrations demonstrated a sigmoidal dependence of the ATeam Förster resonance energy transfer ratio on the intracellular ATP concentration ([ATP]i) with an apparent KD of 2.6 mm, indicating its suitability for [ATP]i measurement. Induction of recurrent network activity resulted in global [Na+]i oscillations with amplitudes of ∼10 mm, encompassing somata and dendrites. These were accompanied by a steady decline in [ATP]i by 0.3–0.4 mm in both compartments. Global [Na+]i transients, induced by afferent fibre stimulation or bath application of glutamate, caused delayed, transient decreases in [ATP]i as well. Brief focal glutamate application that evoked transient local Na+ influx into a dendrite, however, did not result in a measurable reduction in [ATP]i. Our results suggest that ATP consumption by the NKA following global [Na+]i transients temporarily overrides its availability, causing a decrease in [ATP]i. Locally restricted Na+ transients, however, do not result in detectable changes in local [ATP]i, suggesting that ATP production, together with rapid intracellular diffusion of both ATP and Na+ from and to unstimulated neighbouring regions, counteracts a local energy shortage under these conditions.

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“…Intracellular sodium elevations may result in reversal of the NCX, thereby mediating calcium import into astrocytes, which was suggested to contribute to local calcium signaling in astrocyte processes (Boscia et al, 2016;Jackson and Robinson, 2018). We therefore studied the involvement of NCX activity in the generation of NMDA-evoked calcium signals in astrocyte processes.…”

Section: Nmda-induced Ion Signaling and Ncx Activitymentioning

confidence: 99%

Heterogeneity of Activity-Induced Sodium Transients between Astrocytes of the Mouse Hippocampus and Neocortex: Mechanisms and Consequences

et al. 2019

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Activity-related sodium transients induced by glutamate uptake represent a special form of astrocyte excitability. Astrocytes of the neocortex, as opposed to the hippocampus proper, also express ionotropic glutamate receptors, which might provide additional sodium influx. We compared glutamate-related sodium transients in astrocytes and neurons in slices of the neocortex and hippocampus of juvenile mice of both sexes, using widefield and multiphoton imaging. Stimulation of glutamatergic afferents or glutamate application induced sodium transients that were twice as large in neocortical as in hippocampal astrocytes, despite similar neuronal responses. Astrocyte sodium transients were reduced by ϳ50% upon blocking NMDA receptors in the neocortex, but not hippocampus. Neocortical, but not hippocampal, astrocytes exhibited marked sodium increases in response to NMDA. These key differences in sodium signaling were also observed in neonates and in adults. NMDA application evoked local calcium transients in processes of neocortical astrocytes, which were dampened upon blocking sodium/calcium exchange (NCX) with KB-R7943 or SEA0400. Mathematical computation based on our data predict that NMDA-induced sodium increases drive the NCX into reverse mode, resulting in calcium influx. Together, our study reveals a considerable regional heterogeneity in astrocyte sodium transients, which persists throughout postnatal development. Neocortical astrocytes respond with much larger sodium elevations to glutamatergic activity than hippocampal astrocytes. Moreover, neocortical astrocytes experience NMDA-receptor-mediated sodium influx, which hippocampal astrocytes lack, and which drives calcium import through reverse NCX. This pathway thereby links sodium to calcium signaling and represents a new mechanism for the generation of local calcium influx in neocortical astrocytes.Astrocyte calcium signals play a central role in neuron-glia interaction. Moreover, activity-related sodium transients may represent a new form of astrocyte excitability. Here we show that activation of NMDA receptors results in prominent sodium transients in neocortical, but not hippocampal, astrocytes in the mouse brain. NMDA receptor activation is accompanied by local calcium signaling in processes of neocortical astrocytes, which is augmented by sodium-driven reversal of the sodium/calcium exchanger. Our data demonstrate a significant regional heterogeneity in the magnitude and mechanisms of astrocyte sodium transients. They also suggest a close interrelation between NMDA-receptor-mediated sodium influx and calcium signaling through the reversal of sodium/ calcium exchanger, thereby establishing a new pathway for the generation of local calcium signaling in astrocyte processes.

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Regulation of mitochondrial dynamics in astrocytes: Mechanisms, consequences, and unknowns

Cited by 113 publications

References 280 publications

Prokineticin‐2 promotes chemotaxis and alternative A2 reactivity of astrocytes

Prokineticin‐2 promotes chemotaxis and alternative A2 reactivity of astrocytes

Relation between activity‐induced intracellular sodium transients and ATP dynamics in mouse hippocampal neurons

Heterogeneity of Activity-Induced Sodium Transients between Astrocytes of the Mouse Hippocampus and Neocortex: Mechanisms and Consequences

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