. 2017 Feb 8;93(3):587-605.e7.

doi: 10.1016/j.neuron.2016.12.034. Epub 2017 Jan 26.

Transient Opening of the Mitochondrial Permeability Transition Pore Induces Microdomain Calcium Transients in Astrocyte Processes

Amit Agarwal¹, Pei-Hsun Wu², Ethan G Hughes¹, Masahiro Fukaya³, Max A Tischfield⁴, Abraham J Langseth¹, Denis Wirtz², Dwight E Bergles⁵

Affiliations

¹ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Department of Chemical and Biomolecular Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Department of Anatomy, Kitasato University School of Medicine, Sagamihara 252-0374, Japan.
⁴ Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: dbergles@jhmi.edu.

PMID: 28132831
PMCID: PMC5308886
DOI: 10.1016/j.neuron.2016.12.034

Transient Opening of the Mitochondrial Permeability Transition Pore Induces Microdomain Calcium Transients in Astrocyte Processes

Amit Agarwal et al. Neuron. 2017.

. 2017 Feb 8;93(3):587-605.e7.

doi: 10.1016/j.neuron.2016.12.034. Epub 2017 Jan 26.

Authors

Amit Agarwal¹, Pei-Hsun Wu², Ethan G Hughes¹, Masahiro Fukaya³, Max A Tischfield⁴, Abraham J Langseth¹, Denis Wirtz², Dwight E Bergles⁵

Affiliations

¹ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Department of Chemical and Biomolecular Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Department of Anatomy, Kitasato University School of Medicine, Sagamihara 252-0374, Japan.
⁴ Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: dbergles@jhmi.edu.

PMID: 28132831
PMCID: PMC5308886
DOI: 10.1016/j.neuron.2016.12.034

Abstract

Astrocytes extend highly branched processes that form functionally isolated microdomains, facilitating local homeostasis by redistributing ions, removing neurotransmitters, and releasing factors to influence blood flow and neuronal activity. Microdomains exhibit spontaneous increases in calcium (Ca²⁺), but the mechanisms and functional significance of this localized signaling are unknown. By developing conditional, membrane-anchored GCaMP3 mice, we found that microdomain activity that occurs in the absence of inositol triphosphate (IP3)-dependent release from endoplasmic reticulum arises through Ca²⁺ efflux from mitochondria during brief openings of the mitochondrial permeability transition pore. These microdomain Ca²⁺ transients were facilitated by the production of reactive oxygen species during oxidative phosphorylation and were enhanced by expression of a mutant form of superoxide dismutase 1 (SOD1 G93A) that causes astrocyte dysfunction and neurodegeneration in amyotrophic lateral sclerosis (ALS). By localizing mitochondria to microdomains, astrocytes ensure local metabolic support for energetically demanding processes and enable coupling between metabolic demand and Ca²⁺ signaling events.

Keywords: ATP; astrocyte; calcium; cortex; in vivo; metabolism; microdomain; mitochondria; two-photon.

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Figures

**Figure 1. Conditional expression of mGCaMP3 in astrocytes**
(A) Gene trap strategy used to insert conditional mGCaMP3 transgene into murine Rosa26 gene. (Top) mGCaMP3 targeting vector which harbors 5′ short (R26-SA) and 3′ long (R26-LA) homology arms from Rosa26, the CMV enhancer chicken β-actin hybrid (CAG) promoter (black box), loxP (blue triangles) flanked neomycin resistance cassette (NeoR, gray box) flanked by two FRT sites (yellow triangles) and 3x SV40-polyA sequence (red hexagon), the mGCaMP3 cDNA (light green box), woodchuck post-transcriptional response element (WPRE, brown box), bovine growth hormone poly A sequence (red box) and negative selection cassette with diphtheria toxin fragment A (DTA, black box). (Bottom) Rosa26 allele with conditional mGCaMP3 cassette after homologous recombination. NeoR cassette was removed by *in vivo* site-specific recombination. (B) Coronal section of brain from a *GLAST-CreER;Rosa26-lsl-mGCaMP3* (*GLAST-mGC3*) mouse immunostained for mGCaMP3. (C) Coronal hemi-section of brain from a *GLAST-CreER;Rosa26-lsl-mGCaMP3;Rosa26-lsl-tdTomato* (*GLAST-mGC3/tdT*) mouse immunostained for tdTomato, mGCaMP3 and GFAP. Inset shows one cortical astrocyte at higher magnification co-expressing mGCaMP3 and GFAP. (D) High magnification images from boxed area in (C). CC: corpus callosum, CgCx: cingulate cortex. (E) Images showing one cortical astrocyte from a *GLAST-mGC3/tdT* mouse (maximum intensity projected confocal z-stack) immunostained for mGCaMP3 and tdT. (F) Coronal hemi-section of brain from a *GFAP-CreER;Rosa26-lsl-mGCaMP3* (*GFAP-CreER;mGC3*) mouse immunostained for mGCaMP3 and GFAP. (G) Coronal section of brain from a *GLAST-mGC3* mouse showing silver intensified immunogold labeling of mGCaMP3. Inset shows one astrocyte at higher magnification. (H, I) High magnification images of silver intensified immunogold labeling of mGCaMP3 in an astrocyte soma (H) and peri-synaptic processes (I) from *GLAST-mGC3* mice. NT: nerve terminal, Nu: nucleus, Sp: spine.

**Figure 3. Neurotransmitters activate distinct microdomains in astrocyte processes (See also Figure S2 and Movie S2)**
(A) Median intensity projection image (pseudocolored) of 540 frames from one astrocyte from a *GLAST-mGC3* mouse (left). Map of spontaneously active microdomains (in TTX (1 μM)) overlaid on image (right). (B) Map of microdomains recorded in control (119 domains, left) and after application of norepinephrine (0.5 μM NE, 152 domains, right). Dashed lines indicate cell border. (C) Intensity versus time traces for five microdomains (corresponding to colors in B), showing characteristics of Ca²⁺ transients in control and following application of NE. (D) Examples of microdomain Ca²⁺ transients from traces #2 and #5 (asterisks in C). (E) Raster plots displaying timing and intensity of Ca²⁺ transients (119 microdomains in control, left, and 152 microdomains in NE, right). (F) Graph of change in temporal correlation of Ca²⁺ transients among microdomains induced by NE (N = 24 cells, *GLAST-mGC3* mice). Data shown as mean ± SEM. *** p < 0.0001 and * p = 0.01, paired two-tailed Student’s t-test. (G – I) Graphs showing mean duration per event (G), frequency of events per domain (H) and spatial co-localization index (I) in control (+ TTX) and NE (+TTX). Data shown as mean ± SEM (n = 18 cells, *GLAST-mGC3* mice). *** p < 0.0001, paired two-tailed Student’s t-test. (J) Map showing distribution of active microdomains recorded after application of ATP (blue) and NE (red). Microdomains that exhibited activity in both conditions shown in green. (K – M) Graphs comparing co-localization between microdomains recorded in NE (+ TTX) and ATP (+ TTX) (K), NE (+ TTX) and DHPG (+ TTX) (L), ATP (+ TTX) and DHPG (+ TTX) (M). After randomization, the spatial co-localization of microdomains between two conditions was significantly reduced. Data shown as mean ± SEM. N = 9 cells from *GLAST-mGC3* mice. *** p < 0.0004, paired two-tailed Student’s t-test. (N) Graph of number of active domains per cell in control and during two successive applications of ATP (ATP1, ATP2). Data shown as mean ± SEM. N = 15 cells from *GLAST-mGC3* mice. *** p < 0.0001 and ** p < 0.001 repeated measure one-way ANOVA analysis with Tukey’s multiple comparisons post hoc test. (O) Graph of spatial co-localization between active microdomains during two ATP applications. All experiments were done in the presence of TTX. After randomization, the spatial co-localization of microdomains between two conditions was significantly reduced. Data shown as mean ± SEM. N = 15 cells from *GLAST-mGC3* mice. *** p < 0.0001, paired two-tailed Student’s t-test. (P) Temporal correlation of Ca²⁺ transients among microdomains recorded during baseline (Control) and in the presence of metabotropic receptor agonists (ATP, DHPG, and NE; all in TTX). Data shown as mean ± SEM. N = 9 cells from *GLAST-mGC3* mice. *** p = 0.0002, Repeated measures one-way ANOVA with Tukey’s Multiple Comparison Test.

**Figure 4. Spontaneous microdomain Ca²⁺ transients persist in the absence of neurotransmitter release and ER-dependent Ca²⁺ release (See also Figure S3 and Movie S3)**
(A) Spontaneous EPSCs recorded from cortical pyramidal neurons in control conditions (black trace) and after treatment with veratidine (10 μM) and bafilomycin A1 (4 μM, BafA1, red trace). (B) Histogram of the frequency of spontaneous EPSCs recorded in control conditions and after treatment with veratidine and BafA1. Data shown as mean ± SEM. N = 7 (untreated) N = 5 (BafA1) cells from control mice (*GLAST-mGC3* or *mGCaMP3/+*). **p < 0.009, unpaired two-tailed Student’s t-test. (C) Histogram of the amplitudes of spontaneous EPSCs recorded in control conditions and after treatment with veratidine and BafA1. (D) Image of one astrocyte from a *GLAST-mGC3* mouse showing median intensity projection (pseudocolored) from 540 frames (left) in an acute brain slice treated with veratridine and BafA1. (E) Map of 99 spontaneously active microdomains recorded in veratridine and BafA1. (F) Intensity versus time traces of 5 microdomains (corresponding to colors in E) showing characteristics of Ca²⁺ transients in veratridine and BafA1. (G) Raster plot displaying Ca²⁺ transients from 99 microdomains in veratridine and BafA1. (H, I) Graphs of number of microdomains per cell (H) and frequency of events per microdomain (I) recorded in control and in veratridine and BafA1. Data shown as mean ± SEM. N = 33 (untreated) and 36 (BafA1) cells from *GLAST-mGC3* mice. ns: not significant, two-tailed Student’s t-test. (J) Image of one astrocyte from a *GLAST-mGC3;IP₃R2−/−*mouse showing median intensity projection (pseudocolored) from 260 s (left). Map of spontaneously active microdomains (in TTX (1μM)) overlaid on image (right). (K) Map of all spontaneously active microdomains in 260 s (35 domains). Dashed line indicates cell border. (L) Intensity versus time traces of five microdomains (corresponding to colors in B) showing characteristics of Ca²⁺ transients. (M) Raster plot displaying Ca²⁺ transients from active regions in 260 s. (N – Q) Graphs of number of microdomains per cell (N), frequency of events per domain (O), number of Ca²⁺ transients observed per microdomain (P) and mean amplitude (Q) in *GLAST-mGC3* (Control, 94 cells) and *GLAST-mGC3;IP3R2−/−*(104 cells) mice. Data shown as mean ± SEM. *** p < 0.0001, unpaired two-tailed non-parametric Mann-Whitney test. (R – T) Intensity versus time plots for 5 microdomains (top) and raster plots (bottom) displaying spontaneous Ca²⁺ transients (in control, black) and NE (10 μM, green) and ATP (100 μM, orange) from *GLAST-mGC3;IP3R2−/−*mice. All experiments were done in the presence of 1 μM TTX. (U – W) Graphs of number of microdomains per cell (U), frequency of events per domain (V), and mean amplitude (W) of spontaneous Ca²⁺ transients (in TTX, black) and NE (10 μM, green) and ATP (100 μM, orange) from *GLAST-mGC3;IP3R2−/−* mice. Data shown as mean ± SEM. N = 12 cells for each condition. ns: not significant, p > 0.05, ** p < 0.01 and * p < 0.01 repeated measure one-way ANOVA analysis with Tukey’s multiple comparisons post hoc test.

**Figure 5. Microdomain Ca²⁺ transients persist *in vivo* in *IP3R2−/−*mice (See also Movie S4, S5)**
(A) *In vivo* two photon imaging configuration in which mice were allowed to walk on a linear treadmill. (B) Median intensity projection image (pseudocolored) of one astrocyte *in vivo* from the primary visual cortex (V1) in a *GLAST-mGC3;IP3R2+/+* mouse showing active regions during 260 s (left). Map of spontaneously active microdomains is overlaid on image (right). Dashed red line highlights blood vessel. (C) Image of one astrocyte *in vivo* from visual cortex (V1) in a *GLAST-mGC3;IP3R2−/−*mouse, showing median intensity projection (pseudocolored) from 260 s (left). Map of all spontaneously active microdomains (101) that occurred in 286 s is overlaid on image (right). (D) Map of all microdomains (101) that occurred in 286 s in astrocyte shown in (B) (*GLAST-mGC3; IP3R2+/+*) mouse. (E) Intensity versus time plots for five microdomains (corresponding to colors in D) showing characteristics of Ca²⁺ transients in a *GLAST-mGC3;IP₃R2+/*+ mouse (top). Raster plot displaying the activity of all microdomains (bottom). Timing of enforced locomotion highlighted by dashed line. (F) Map of all microdomains (51) that occurred in 286 s in astrocyte shown in (C) (*GLAST-mGC3;IP3R2−/−*) mouse. (G) Intensity versus time plots for five microdomains (corresponding to colors in F) showing characteristics of Ca²⁺ transients from cell in (F) (top). Raster plot displaying the activity of all microdomains (bottom). Timing of enforced locomotion highlighted by dashed line. (H) Histograms of the average number of active microdomains per cell (left) and number of Ca²⁺ transients (Events) during 50 s of imaging (right), in *IP3R2+/+* (*GLAST-mGC3;IP3R2+/+*) and *IP3R2−/−*(*GLAST-mGC3;IP3R2−/−*) mice during baseline activity. Data shown as mean ± SEM. N = 14 cells from *GLAST-mGC3;IP₃R2+/*+ mice and 25 cells from *GLAST-mGC3;IP3R2−/−*mice were analyzed. ns: not significant, * p > 0.05, unpaired two-tailed Student’s t-test. (I – J) Graphs showing the number of Ca²⁺ transients (Events) observed during 50 s of imaging (I) and mean amplitude (z-score) for microdomain Ca²⁺ transients (J) without stimulation (spontaneous, Spont) and during enforced locomotion on the treadmill (TM) for Control (*IP3R2+/+*) (left) and *IP3R2−/−*mice (right). Data shown as mean ± SEM. Note change in scale for the *IP3R2−/−*mice in (I). N = 13 cells from *GLAST-mGC3;IP3R2+/*+ mice and 14 cells from *GLAST-mGC3;IP3R2−/−*mice were analyzed. ns: not significant, p > 0.05, ** p < 0.009, *** p < 0.0001, paired two-tailed Student’s t-test.

**Figure 6. Microdomain Ca²⁺ transients co-localize with mitochondria (See also Figure S4 and Movie S6)**
(A) Electron micrograph showing silver enhanced gold immunolabeling of mGCaMP3 in a *GLAST-mGC3* mouse. Astrocyte processes are colored red and mitochondria in astrocyte processes are colored green. Yellow arrows highlight excitatory synapses. Image at right shows higher magnification image of area highlighted by boxed area at left. (B) Electron micrographs showing spatial relationship between mitochondria and ER in astrocyte processes located in the vicinity of the excitatory nerve terminals. (C) Histogram showing area within fine astrocyte processes and nerve terminals occupied by mitochondria. Data shown as mean ± SEM. ns: not significant, p > 0.05 unpaired two-tailed Student’s t-test. (D) Images of cortical astrocytes from a *GLAST-CreER;Rosa26-lsl-tdTomato;Rosa26-lsl-mito-EGFP* (*GLAST-tdT;mito-EGFP*) mouse labeled with anti-GFAP (GFAP, blue), anti-mCherry (tdT, red) and anti-GFP antibodies. (E) High magnification images of one astrocyte (highlighted by box in E) showing tdT, mGCaMP3 and GFAP localization. (F) Image of one astrocyte in a *GLAST-mGC3;mito-EGFP* mouse showing median intensity projection (pseudocolored) from 260 s (top). Map of spontaneously active microdomains is overlaid on image (below). Dashed white line highlights cell border. (G) Image of fluorescently tagged mitochondria from cell in (F) (top). Map of spontaneously active microdomains (mD, outlined in black) and mitochondria (Mito, green). (H) Image of fluorescently tagged mitochondria in which z plane has been expanded to visualize mitochondria just above and below plane of imaging from cell in (F) (top). Map of spontaneously active microdomains (mD, outlined in black) and mitochondria (Mito, green). Additional co-localized areas highlighted in red. (I) Intensity versus time plots for Ca²⁺ transients from five microdomains (colors correspond to locations shown in F, bottom), showing characteristics of spontaneous Ca²⁺ signals. (J) Plot of co-localization between spontaneously active microdomains and mitochondria and co-localization after randomization of mitochondrial locations within the imaging plane (blue) and after z adjustment (green). Data shown as mean ± SEM. N = 7 cells (single plane) and N = 12 cells (z-plane corrected) from *GLAST-mGC;mito-EGFP* mice. *** p < 0.0001, paired two-tailed Student’s t-test. (K) Histogram showing the decrease in active microdomains that did not co-localize with mitochondria after treatment with thapsigargin (Tpg, 1 μM, 60 minutes) to deplete ER Ca²⁺ stores. Data shown as mean ± SEM, N = 12 (untreated) and 11 (Tpg treated) cells. * p < 0.03, unpaired two-tailed Student’s t-test.

**Figure 7. Mitochondrial membrane permeability transition pore (mPTP) regulates spontaneous Ca²⁺ transients (See also Figure S5–S7 and Movie S7, S8)**
(A) Schematic showing configuration of membrane permeability transition pore (mPTP, red), mitochondrial Ca²⁺ uniporter (MCU, yellow) and the electron transport chain (ETC, blue). Pharmacological inhibition of mPTP (mPTP-I; cyclosporin A, 20 μM and rotenone, 10 μM) inhibits mPTP opening and prevents Ca²⁺ efflux from mitochondrial matrix into the cytosol. (B) Images of astrocytes (median intensity projection of time-series image stack) showing active regions during 286 s in control (left) and after exposure to mPTP-I (right) (*GLAST-mGC3;IP3R2−/−*mouse). (C) Maps of all spontaneously active microdomains in control (28) and after mPTP inhibition (4). (D) Intensity versus time plots for five microdomains in control and four microdomains in mPTP-I treated slices (colors correspond to locations shown in C). (E) Raster plot displaying Ca²⁺ transients from all active regions in 286 s in control (top) and mPTP-I (bottom) treated slices. (F) Graphs showing relative frequency (left) and mean amplitude (z-score) of Ca²⁺ transients in control and mPTP-I treated slices. Data shown as mean ± SEM. N = 18 cells. *** p < 0.0001, ** p < 0.001, unpaired two-tailed Student’s t-test. (G) Schematic showing enhancement of mPTP opening by carboxyatratyloside (CAtr, 20 μM), leading to enhanced Ca²⁺ efflux from the mitochondrial matrix to the cytosol. (H) Image of an astrocyte (median intensity projection of time-series image stack) showing active regions during 286 s in a *GLAST-mGC3;IP3R2−/−*mouse. (I) Maps of all spontaneously active microdomains during 260 s in control (19) and after mPTP activation (70) (CAtr treated). (J) Intensity versus time plots of microdomain activity in control (left) and after CAtr treatment (right) (colors correspond to locations shown in I). (K) Raster plots displaying Ca²⁺ transients in an astrocyte in control (top) and after CAtr treatment (bottom). (L) Graphs showing changes in number of active microdomains per cell (left), event frequency per microdomain (middle), and mean amplitude of Ca²⁺ transients (right) recorded in control and after CAtr treatment. Data shown as mean ± SEM. For each condition 10 individual cells from *GLAST-mGC3;IP3R2−/−*mice were analyzed. ns: not significant, ** p < 0.006, paired two-tailed Student’s t-test. (M) Image of an astrocyte (median intensity projection of time-series image stack) showing active regions during 286 s in a *GLAST-mGC3;IP3R2−/−*mouse. (N) Maps of all spontaneously active microdomains during 260 s in control (left), after light exposure (Photoact., middle), and after mPTP-I treatment (right). (O) Raster plots displaying Ca²⁺ transients in an astrocyte in control (left), after light exposure (Photoact., middle), and after mPTP-I treatment (right). (P) Graphs showing changes in number of domains per cell (top) and event frequency/domain (bottom) in control, after light exposure (Photoact.), and after mPTP-I treatment. Data shown as mean ± SEM. N = 10 cells from *GLAST-mGC3;IP3R2−/−*mice. ns: not significant, *** p <0.0001, * p < 0.01 repeated measure one-way ANOVA analysis with Tukey’s multiple comparisons post hoc test.

**Figure 8. Enhanced mitochondrial Ca²⁺ efflux from astrocytes in ALS model (*SOD1^G93A*) mice (See also Figure S8)**
(A) Schematic showing the *in vivo* two photon imaging configuration in which mice were allowed to walk on a linear treadmill. (B) Intensity versus time plots of microdomain activity in an astrocyte from a control mouse (top) and from a *SOD1^G93A* mouse (bottom). (C) Raster plots displaying Ca²⁺ transients in astrocyte microdomains from a control mouse (left) and from a *SOD1^G93A* mouse (right). (D, E) Graphs of the number of active microdomains per cell (D) and frequency of events per microdomain (E) in control and *SOD1^G93A* mice. Data shown as mean ± SEM. N = 11 cells each from *Control* and *SOD1^G93A* mice. * p < 0.01, ** p < 0.001 unpaired two-tailed Student’s t-test. (F) Images of single astrocytes in acute slices of motor cortex from a *GLAST-mGC3* (top) and a *SOD1^G93A* mouse (bottom) showing median intensity projection (pseudocolored) from 260 s after treatment with thapsigargin (Tpg, 1 μM, 60 minutes). (G) Maps of all active microdomains (Control: 22; *SOD1^G93A*: 39) that occurred in 286 s in astrocytes shown in (F). (H) Intensity versus time plots of microdomain activity in a control (top) and in a *SOD1^G93A* mouse (bottom) (colors correspond to locations shown in corresponding maps in G). (I) Raster plots displaying microdomain Ca²⁺ transients imaged over a period of 260 s recorded in Tpg in a control (top) and in a *SOD1^G93A* mouse (bottom). (J) Graphs comparing the frequency (left) and mean amplitude (z-score, right) of microdomain Ca²⁺ transients in Tpg treated cortical slices from aged matched control and *SOD1^G93A* mice. Data shown as mean ± SEM. N = 14 cells each from *Control* and *SOD1^G93A* mice. * p < 0.03, unpaired two-tailed Student’s t-test. (K) Graphs comparing the frequency (left) and mean amplitude (z-score, right) of microdomain Ca²⁺ transients in *SOD1^G93A* mice before (baseline) and after mPTP inhibition (mPTP-I, 30 min). Data shown as mean ± SEM. N = 10 cells each from *Control* and *SOD1^G93A* mice. * p <0.02, ** p < 0.002, paired two-tailed Student’s t-test.

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Mitochondrial Calcium Sparkles Light Up Astrocytes.
MacVicar BA, Ko RW. MacVicar BA, et al. Dev Cell. 2017 Feb 27;40(4):327-328. doi: 10.1016/j.devcel.2017.02.013. Dev Cell. 2017. PMID: 28245918

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Transient Opening of the Mitochondrial Permeability Transition Pore Induces Microdomain Calcium Transients in Astrocyte Processes

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Transient Opening of the Mitochondrial Permeability Transition Pore Induces Microdomain Calcium Transients in Astrocyte Processes

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