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. 2017 Apr;65(4):569-580.
doi: 10.1002/glia.23112. Epub 2017 Jan 28.

Neuron-astrocyte signaling is preserved in the aging brain

Marta Gómez-Gonzalo  1 , Mario Martin-Fernandez  2 , Ricardo Martínez-Murillo  1 , Sara Mederos  1 , Alicia Hernández-Vivanco  1 , Stephanie Jamison  2 , Ana P Fernandez  1 , Julia Serrano  1 , Pilar Calero  1 , Hunter S Futch  3 , Rubén Corpas  4 , Coral Sanfeliu  4 , Gertrudis Perea  1 , Alfonso Araque  2
Affiliations

Neuron-astrocyte signaling is preserved in the aging brain

Marta Gómez-Gonzalo et al. Glia. 2017 Apr.

Abstract

Astrocytes play crucial roles in brain homeostasis and are emerging as regulatory elements of neuronal and synaptic physiology by responding to neurotransmitters with Ca2+ elevations and releasing gliotransmitters that activate neuronal receptors. Aging involves neuronal and astrocytic alterations, being considered risk factor for neurodegenerative diseases. Most evidence of the astrocyte-neuron signaling is derived from studies with young animals; however, the features of astrocyte-neuron signaling in adult and aging brain remain largely unknown. We have investigated the existence and properties of astrocyte-neuron signaling in physiologically and pathologically aging mouse hippocampal and cortical slices at different lifetime points (0.5 to 20 month-old animals). We found that astrocytes preserved their ability to express spontaneous and neurotransmitter-dependent intracellular Ca2+ signals from juvenile to aging brains. Likewise, resting levels of gliotransmission, assessed by neuronal NMDAR activation by glutamate released from astrocytes, were largely preserved with similar properties in all tested age groups, but DHPG-induced gliotransmission was reduced in aged mice. In contrast, gliotransmission was enhanced in the APP/PS1 mouse model of Alzheimer's disease, indicating a dysregulation of astrocyte-neuron signaling in pathological conditions. Disruption of the astrocytic IP3 R2 mediated-signaling, which is required for neurotransmitter-induced astrocyte Ca2+ signals and gliotransmission, boosted the progression of amyloid plaque deposits and synaptic plasticity impairments in APP/PS1 mice at early stages of the disease. Therefore, astrocyte-neuron interaction is a fundamental signaling, largely conserved in the adult and aging brain of healthy animals, but it is altered in Alzheimer's disease, suggesting that dysfunctions of astrocyte Ca2+ physiology may contribute to this neurodegenerative disease. GLIA 2017 GLIA 2017;65:569-580.

Keywords: astrocytes; brain aging; gliotransmission; neuron-glia signaling; synaptic plasticity.

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Conflict of interest statement

The authors have no conflict of interest to declare.

Figures

Figure 1
Figure 1. Spontaneous Ca2+ signals in astrocytes during aging
A: Scheme of different lifetime points selected for analysis. B: Left, pseudocolor images of hippocampal astrocytes (5-month old mouse) showing the colocalization of SR-101 and Fluo-4 fluoresecence signals at the soma of numbered astrocytes. Parenchymal blood vessels filled with SR101 are indicated (asterisk). Scale bar, 20 µm. Right, time course of the intracellular Ca2+ signals from astrocytes indicated in A. Note the presence of spontaneous Ca2+ oscillations in some astrocytes. C–D: Mean percentage of active astrocytes and Ca2+ oscillation frequency at different mice ages for hippocampus (C; n = 90, 86, 118 and 68 astrocytes from 0.5, 5, 12 and 20-month old mice, respectively), and cortex (D; n = 71, 60, 77 and 66 astrocytes from 0.5, 5, 12 and 20-month old mice, respectively). *p < 0.05; **p < 0.01; ***p < 0.001; unpaired t-test and Mann-Whitney rank-sum test. Error bars indicate SEM.
Figure 2
Figure 2. Neuron-Astrocyte Ca2+ signaling sensitivity during aging
A: Top, pseudocolor images of fluo-4- and SR-101-filled cortical astrocytes (5-month old mouse; scale bar, 15µm). Bottom, Ca2+ images and raw traces of labeled astrocytes before and after ATP stimulation (arrows; scale bar, 10 µm). B: Astrocyte Ca2+ spike probability to neurotransmitter receptor activation at different ages: ATP (4 mM; n ≥ 25 astrocytes) ACh (2 mM; n ≥ 16 astrocytes), and TFLLR (1 mM; n ≥ 35 astrocytes). C: Mean percentage of responsive astrocytes shown in B to the different agonist vs age. *p < 0.05; **p < 0.01; ANOVA followed by Student-Newman-Keuls test. D: Astrocyte Ca2+ spike probability to local application of DHPG (1 mM) during aging in hippocampus (n ≥ 53 astrocytes) and cortex (n ≥ 89 astrocytes). E: Mean percentage of responsive astrocytes shown in D to DHPG vs age. *p < 0.05; **p < 0.01; ***p < 0.001. ANOVA; followed by Student-Newman-Keuls test. F: Mean percentage of responsive astrocytes to DHPG in adult mice (5-month-old) in control conditions (n = 152; astrocytes; black bar), in MPEP (50 µM) + LY367385 (100 µM) (n = 79; astrocytes; dashed bar), and in IP3R2−/− mice (n = 25; astrocytes; white bar). *p < 0.05; ***p < 0.001. ANOVA; followed by Student-Newman-Keuls test. Error bars indicate SEM.
Figure 3
Figure 3. Astrocyte synaptic Ca2+ responses and gliotransmission during aging
A: Top, Pseudocolor images of fluo-4- and SR-101-filled hippocampal astrocytes (5-month old mouse. Scale bar, 25 µm), and Ca2+ images and raw traces of labeled astrocytes before and after Schaffer collateral (SC) stimulation (30 Hz, 5s; gray bar. Scale bar, 10 µm). Parenchymal blood vessels filled with SR101 are indicated (asterisk). Bottom, Whole-cell recordings from CA1 pyramidal cell showing neuronal activity induced during SC stimulation (30 Hz, 5 s; gray bar). B: Mean percentage of responding astrocytes to SC synaptic stimulation during aging, in wild type mice (white) and in IP3R2−/− mice (black; n ≥ 32 and n ≥ 33 astrocytes for each condition in wild type and IP3R2−/− mice, respectively). **p<0.01; #p < 0.001; Mann-Whitney rank-sum test. C: Top, Representative whole-cell recordings from CA1 hippocampal neurons from a 5 month-old mouse showing miniature excitatory currents (mEPSCs) and spontaneous SICs (down triangles), in control conditions and in the presence of the NMDAR antagonist AP5 (50 µM; gray trace). Note the absence of SICs in the presence of AP5. Bottom, Mean of SIC frequency at different ages in wild type mice (white; n ≥ 16 neurons for each condition) and in IP3R2−/− mice (black; n ≥ 11). Note the absence of statistical differences; unpaired t-test. D: Mean astrocytic Ca2+ oscillation frequency from IP3R2−/− mice at different ages (n = 23, 49, 64 and 70 astrocytes from 0.5, 5, 12 and 20-month old mice; respectively); p > 0.05; ANOVA followed by Student-Newman-Keuls test. E: Representative recordings from cortical neurons of SICs (down triangles), showing an increase in frequency after DHPG (1 mM) local stimulation. F: Mean frequency of hippocampal and cortical SICs in control and after DHPG stimulation (blue) in wild type mice (n ≥ 5 neurons for each condition) and in IP3R2−/− mice (n ≥ 5) at different ages. *p < 0.05; **p < 0.01; paired t-test. G: Representative recordings from CA1 hippocampal neurons from a 6 month-old SAMP8 mouse showing spontaneous SICs (down triangles), and the SIC frequency average in SAMP8 mice (black; n = 6 neurons) and SAMR1 age-matched control mice (white; n = 7 neurons) in hippocampus and cortex. Note the absence of statistical differences; unpaired t-test. Error bars indicate SEM.
Figure 4
Figure 4. Astrocyte-neuron signaling dysfunction in APP/PS1 AD mouse model
A: Representative recordings from 12-month old APP/PS1 cortical neurons of SICs (down triangles) in control (black trace) and after local stimulation with DHPG (1 mM; gray trace). B: Average of cortical and hippocampal SIC frequency in control (white) and after DHPG stimulation in APP/PS1 mice (dashed; n ≥ 8 neurons for each condition), and compared with age-matched wild type mice (black; n ≥ 6). *p < 0.05; **p < 0.01; ***p < 0.001. ANOVA followed by Student-Newman-Keuls test. C: Representative fluorescence Thioflavin S staining images showing the Aβ deposits (green) in cortex and hippocampus of APP/PS1+/+-IP3R2+/+ and APP/PS1+/+-IP3R2−/− mice at 6-month old (c1, c2), and 2.5 month-old (c3, c4), respectively. Note the remarkable deposition of Thioflavin S-positive Aβ plaques in APP/PS1+/+-IP3R2−/− mice (c2 and c4; arrows). Scale bar, 1 mm. D: Mean values of plaque load in cortex and hippocampus in APP/PS1+/+-IP3R2−/− and APP/PS1+/+-IP3R2+/+ mice (n = 8). **p < 0.01; ***p < 0.001; ANOVA followed by Bonferroni’s test. E: Top, Protein detection of IP3R2 in APP/PS1+/+-IP3R2+/+ and APP/PS1+/+-IP3R2 −/��� mice by immunohistochemistry. Representative sections obtained from the same mice as shown in C, showing that APP/PS1+/+-IP3R2+/+ mice exhibit immunoreaction product labeling astrocytes (white arrows) located in CA3 hippocampal region, while APP/PS1+/+-IP3R2−/− did not show immunoreactivity for IP3R2 labeling. Scale bar, 100 µm. Inset, magnification picture showing a punctate pattern of IP3R2 protein in astrocyte cell body and processes. Scale bar, 10 µm. Bottom, PCR amplification of the IP3R2 wildtype gene and mutant allele from DNA obtained from brain sections shown in C. As expected, PCR confirms the specific ~200bp and ~400bp bands for IP3R2+/+ and IP3R2−/− mice, respectively. C+,C- indicates positive and negative controls. F: Top, Representative fEPSP traces before (a, c) and after (b,d) high frequency stimulation (HFS) protocol in hippocampal slices from APP/PS1+/+-IP3R2−/− mice (blue), and APP/PS1+/+-IP3R2+/+ (red) at 10 weeks. Bottom, Relative fEPSP slope (from basal values) versus time in APP/PS1+/+-IP3R2−/− mice (n = 12 slices from 4 mice; blue); APP/PS1+/+-IP3R2+/+ mice (n = 9 slices from 3 mice; red); APP/PS1−/−-IP3R2−/− mice (n = 14 slices from 4 mice; black); APP/PS1−/−-IP3R2+/+ mice (n = 12 slices from 4 mice; gray). Zero time corresponds to the onset of HFS. G: Relative changes of the fEPSP slope in APP/PS1+/+-IP3R2−/− mice and corresponding littermates shown in E. Error bars indicate SEM. ** p<0.01; ***p < 0.001; paired t-test.
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