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. 2014 Sep 17;34(38):12738-44.
doi: 10.1523/JNEUROSCI.2401-14.2014.

Structural and functional plasticity of astrocyte processes and dendritic spine interactions

Alberto Perez-Alvarez  1 , Marta Navarrete  2 , Ana Covelo  3 , Eduardo D Martin  4 , Alfonso Araque  5
Affiliations

Structural and functional plasticity of astrocyte processes and dendritic spine interactions

Alberto Perez-Alvarez et al. J Neurosci. .

Erratum in

  • J Neurosci. 2014 Oct 15;34(42):14163

Abstract

Experience-dependent plasticity of synaptic transmission, which represents the cellular basis of learning, is accompanied by morphological changes in dendritic spines. Astrocytic processes are intimately associated with synapses, structurally enwrapping and functionally interacting with dendritic spines and synaptic terminals by responding to neurotransmitters and by releasing gliotransmitters that regulate synaptic function. While studies on structural synaptic plasticity have focused on neuronal elements, the structural-functional plasticity of astrocyte-neuron relationships remains poorly known. Here we show that stimuli inducing hippocampal synaptic LTP enhance the motility of synapse-associated astrocytic processes. This motility increase is relatively rapid, starting <5 min after the stimulus, and reaching a maximum in 20-30 min (t(1/2) = 10.7 min). It depends on presynaptic activity and requires G-protein-mediated Ca(2+) elevations in astrocytes. The structural remodeling is accompanied by changes in the ability of astrocytes to regulate synaptic transmission. Sensory stimuli that increase astrocyte Ca(2+) also induce similar plasticity in mouse somatosensory cortex in vivo. Therefore, structural relationships between astrocytic processes and dendritic spines undergo activity-dependent changes with metaplasticity consequences on synaptic regulation. These results reveal novel forms of synaptic plasticity based on structural-functional changes of astrocyte-neuron interactions.

Keywords: astrocyte; astrocyte–neuron interactions; dendritic spines; remodeling.

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Figures

Figure 1.
Figure 1.
Synaptic transmission plasticity correlates with astrocytic process remodeling. a, Left, Infrared image showing the recorded pyramidal neuron and stimulation electrode. Right, Alexa Fluor 488-filled neuron (green) and stratum radiatum astrocytes stained with SR101 (red). Scale bar, 40 μm. b, Dendritic spines (green) and astrocytic processes (red). Scale bars: 5 and 2 μm, respectively. c, EPSCs before and 30 min after delivering a HFS protocol. d, Relative EPSC amplitudes in unstimulated (n = 6) and HFS (n = 7) slices. Zero time corresponds to the onset of the HFS protocol. e, Astrocytic process (red) remodeling in the surrounding of excitatory synapses (green) after plasticity induction. Scale bar, 1 μm. f, Average relative changes of displaced processes (n = 6 unstimulated, white bars; n = 28, HFS, red bars). g, h, Displacement amplitude histograms (bin width: 0.05 μm) and corresponding cumulative probability plots showing the percentage and distance traveled by astrocytic processes in unstimulated (n = 5) and HFS-stimulated (n = 22) slices at t = 30 min. i, Time-lapse changes in astrocytic process position after induction of plasticity (n = 5). j, Relative changes of displaced processes in control (n = 7), AP5 (n = 5), TTX (n = 5), MPEP + LY367385 (n = 5), and IP3R2−/− mice (n = 6). Significant differences were established at **p < 0.01.
Figure 2.
Figure 2.
STDP correlates with astrocytic process remodeling. a, EPSCs before (left) and 30 min after (right) STDP protocol (top). b, Relative EPSC amplitudes in slices from wild-type (WT; n = 5) and IP3R2−/− (n = 6) mice. Zero time corresponds to the onset of the STDP protocol. c, Dendritic spines (green) and astrocytic processes (red) before (left) and 30 min after (right) delivering the STDP protocol in wild-type mice. Scale bar, 1 μm. d, Quantification of displaced processes in unstimulated (n = 6) and STDP-stimulated (n = 5) slices from wild-type mice. e, f, As in c, d, respectively, but in slices from IP3R2−/− mice. Scale bar, 2 μm. Significant differences were established at *p < 0.05.
Figure 3.
Figure 3.
Astrocytic modulation of synaptic transmission is impaired after LTP protocol. a, Scheme of paired-recorded pyramidal neurons and the stimulating electrodes. b, Responses evoked by minimal stimulation (top traces) and average EPSCs (n = 60 stimuli, including successes and failures; bottom traces) before (basal), after first ND, 30 min after HFS (Basal After Plasticity), and after second ND. c, Synaptic efficacy (i.e., mean amplitude of responses including successes and failures of neurotransmission) before, after first ND, 30 min after HFS, and after second ND (n = 7). First and second NDs were delivered at 0 and 36 min, respectively. d, Relative changes from control basal values of synaptic parameters after first and second ND in unstimulated (n = 7), HFS (n = 7), and STDP (n = 5)-stimulated slices. Pr, Probability of release. e, Fluorescence intensities of Fluo-4-filled astrocytes before and after first and second ND. Scale bar, 10 μm. f, Astrocyte Ca2+ spike probability in unstimulated (111 astrocytes, n = 11 slices) and HFS conditions (71 astrocytes, n = 8 slices). Zero time corresponds to the beginning of ND. g, Ca2+ spike probability before (basal; white bars) and after first (striped bars) and second ND (n = 5; filled bars) in unstimulated (n = 11) and HFS (n = 8) or STDP (n = 6)-stimulated. h, Relative synaptic efficacy evoked by minimal stimulation versus time before (basal, black circles), after first stimuli (first HFS, blue circles), and after second stimuli (second HFS, red circles; n = 4). Zero time corresponds to the onset of first HFS. Note that the system is not saturated after first stimulation. i, Relative changes from control values (basal, black bars) of synaptic parameters after first (blue bars) and second (red bars) HFS (n = 4). Significant differences were established at *p < 0.05, **p < 0.01, and #p < 0.001.
Figure 4.
Figure 4.
In vivo sensory stimulation correlates with astrocytic process remodeling in primary somatosensory cortex. a, Scheme of the in vivo imaging. b, c, Images at different magnification of in vivo astrocytes and processes stained with SR101 (red) and dendrites (green). Scale bars: b, left, 10 μm; right, 5 μm; c, 2 μm. d, LFP responses to whisker stimulation before and after sensory stimulation. e, Relative LFP responses (n = 5) before and after sensory stimulation at t = 0. f, Representative example of in vivo astrocytic process displacement after sensory stimulation. Scale bar, 1 μm. g, Displaced processes 30 min after sensory stimulation in unstimulated (n = 4), and stimulated in control (n = 4), MPEP + LY367385 (n = 8), and in the IP3R2−/− mice (n = 4). h, Displacement amplitude histograms (bin width: 0.05 μm) of in vivo astrocytic processes in unstimulated and sensory-stimulated mice (t = 30 min). i, In vivo images of Fluo-4-filled astrocytes before and after sensory stimulation from wild-type and IP3R2−/− mice. Scale bar, 10 μm. j, Ca2+ levels from four astrocytes from wild-type (black traces) and IP3R2−/− mice (red traces). Horizontal bar indicates sensory stimulation. k, Responding astrocytes from wild-type (top; 85 astrocytes, n = 4 mice) and IP3R2−/− mice (bottom; 67 astrocytes, n = 3 mice) in unstimulated and sensory stimulation conditions. Significant differences were established at *p < 0.05, **p < 0.01.
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