Ion changes and signalling in perisynaptic glia
ABSTRACT The maintenance of ion gradients across plasma membranes is a prerequisite for the establishment of cellular membrane potentials, electrical signalling, and metabolite transport. At active synapses, pre- and postsynaptic ion gradients are constantly challenged and used for signalling purposes. Perisynaptic glia, mainly represented by fine processes of astrocytes which get into close vicinity to neuronal synapses, are required to normalize the extracellular ionic milieu and maintain ion gradients. On the other hand, perisynaptic glia itself is activated by synaptically released transmitters binding to plasma membrane receptors and transmitter carriers, and experiences significant ion changes as well. In this review we present an overview of dynamic changes of the major ion species in astrocytes in response to neuronal, especially synaptic, activity. We will focus on calcium, sodium, and proton/hydroxyl ions that play key roles in signalling processes, and will discuss the functional consequences of the glial ion signals and homeostatic processes for synaptic transmission.
- SourceAvailable from: Alexei Verkhratsky
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- "The most primary and fundamental astroglial function lies in providing the homeostasis of the central nervous system (CNS). Numerous molecular cascades expressed (often specifically) in astrocytes control interstitial concentration of principal ions, regulate movement and metabolism of major neurotransmitters, supply neurones with energy substrates and contribute to tissue defence through, for example, secreting scavengers of reactive oxygen species (Deitmer and Rose, 2010; Rose et al., 2013; Verkhratsky et al., 2015). Astroglial cells are involved in regulation of interstitial pH by transporting both protons (mostly through sodium-proton transporter 1, NHE1, glutamate transporters EAAT1/2 and proton-lactate co-transporter MCT1) and bicarbonate (through the sodium-bicarbonate co-transporter NBC or the chloride-bicarbonate exchanger AE; see (Deitmer and Chesler, 2009; Deitmer and Rose, 2010)). "
ABSTRACT: Clinical evidence suggest astrocytic abnormality in major depression (MD) while treatment with anti-psychotic drugs affects astroglial functions. Astroglial cells are involved in pH homeostasis of the brain by transporting protons (through sodium-proton transporter 1, NHE1, glutamate transporters EAAT1/2 and proton-lactate co-transporter MCT1) and bicarbonate (through the sodium-bicarbonate co-transporter NBC or the chloride-bicarbonate exchanger AE). Here we show that chronic treatment with fluoxetine increases astroglial pHi by stimulating NHE1-mediated proton extrusion. At a clinically relevant concentration of 1 μM, fluoxetine significantly increased astroglial pHi from 7.05 to 7.34 after 3 weeks and from 7.18 to 7.58 after 4 weeks of drug treatment. Stimulation of NHE1 is a result of transporter phosphorylation mediated by several intracellular signaling cascades that include MAPK/ERK1/2, PI3K/AKT and ribosomal S6 kinase (RSK). Fluoxetine stimulated phosphorylation of ERK1/2, AKT and RSK in a concentration dependent manner. Positive crosstalk exists between two signal pathways, MAPK/ERK1/2 and PI3K/AKT activated by fluoxetine since ERK1/2 phosphrylation could be abolished by inhibitors of PI3K, LY294002 and AKT, triciribine, and AKT phosphorylation by inhibitor of MAPK, U0126. As a result, RSK phosphorylation was not only inhibited by U0126 but also by inhibitor of LY294002. The NHE1 phoshorylation resulted in stimulation of NHE1 activity as revealed by the NH4Cl-prepulse technique; the increase of NHE1 activity was dependent on fluoxetine concentration, and could be inhibited by both U0126 and LY294002. Our findings suggest that regulation of astrocytic pHi and brain pH may be one of the mechanisms underlying fluoxetine action.Frontiers in Cellular Neuroscience 03/2015; 9:61. DOI:10.3389/fncel.2015.00061 · 4.18 Impact Factor
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- "Astrocyte processes show a high degree of rapid motility at synapses (Hirrlinger et al., 2004; Haber et al., 2006), and LTP induction or prolonged stimulation have been shown to give rise to enhanced synaptic ensheathment by astrocyte processes (Wenzel et al., 1991; Genoud et al., 2006; Lushnikova et al., 2009). Fast structural rearrangements at synapses following induction of synaptic potentiation or depression could influence the activation of metabotropic glutamate receptors and calcium signaling in perisynaptic glial processes (Deitmer and Rose, 2010). In this study, we therefore analyzed calcium transients in astrocytes located in the stratum radiatum in response to moderate stimulation of Schaffer collaterals before and after induction of potentiation or depression at Schaffer collateral to CA1 pyramidal cell synapses. "
ABSTRACT: Glial cells respond to neuronal activity by transient increases in their intracellular calcium concentration. At hippocampal Schaffer collateral to CA1 pyramidal cell synapses, such activity-induced astrocyte calcium transients modulate neuronal excitability, synaptic activity, and LTP induction threshold by calcium-dependent release of gliotransmitters. Despite a significant role of astrocyte calcium signaling in plasticity of these synapses, little is known about activity-dependent changes of astrocyte calcium signaling itself. In this study, we analyzed calcium transients in identified astrocytes and NG2-cells located in the stratum radiatum in response to different intensities and patterns of Schaffer collateral stimulation. To this end, we employed multiphoton calcium imaging with the low-affinity indicator dye Fluo-5F in glial cells, combined with extracellular field potential recordings to monitor postsynaptic responses to the afferent stimulation. Our results confirm that somata and processes of astrocytes, but not of NG2-cells, exhibit intrinsic calcium signaling independent of evoked neuronal activity. Moderate stimulation of Schaffer collaterals (three pulses at 50 Hz) induced calcium transients in astrocytes and NG2-cells. Astrocyte calcium transients upon this three-pulse stimulation could be evoked repetitively, increased in amplitude with increasing stimulation intensity and were dependent on activation of metabotropic glutamate receptors. Activity-induced transients in NG2-cells, in contrast, showed a rapid run-down upon repeated three-pulse stimulation. Theta burst stimulation and stimulation for 5 min at 1 Hz induced synaptic potentiation and depression, respectively, as revealed by a lasting increase or decrease in population spike amplitudes upon three-pulse stimulation. Synaptic plasticity was, however, not accompanied by corresponding alterations in the amplitude of astrocyte calcium signals. Taken together, our results suggest that the amplitude of astrocyte calcium signals reflects the number of activated synapses but does not correlate with the degree of synaptic potentiation or depression at Schaffer collateral to CA1 pyramidal cell synapses.Hippocampus 01/2012; 22(1):29-42. DOI:10.1002/hipo.20843 · 4.30 Impact Factor
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- "The maintenance of ion gradients across plasma membranes by passive mechanisms, the activity of ionic pumps and transporters is a prerequisite for the establishment of cellular membrane potentials, electrical signalling, and metabolite transport. On the other hand, electrical signalling and synaptic transmission by neurons, are based on, and result in, ion flow across the plasma membrane, resulting in significant changes in ion concentrations in the extracellular space with modification of ion gradients during neuronal activity (Deitmer and Rose 2010). The effect of activity-induced ion movements on extraand intracellular ion concentrations and their electrochemical gradients, respectively, not only depends on the surfaceto-volume-ratio of the involved compartments, but also on parameters influencing ion diffusion such as buffering and spatial restrictions due to a complex morphology or a dense extracellular perineuronal net (Syková and Chvátal 1993; Syková 1997; Syková and Nicholson 2008). "
ABSTRACT: Astrocytes play a critical role in CNS metabolism, regulation of volume and ion homeostasis of the interstitial space. Of special relevance is their clearance of K(+) that is released by active neurons into the extracellular space. Mathematical analysis of a modified Nernst equation for the electrochemical equilibrium of neuronal plasma membranes, suggests that K(+) uptake by glial cells is not only relevant during neuronal activity but also has a non-neglectable impact on the basic electrical membrane properties, specifically the resting membrane potential, of neurons and might be clinically valuable as a factor in the genetics and epigenetics of the epilepsy and tuberous sclerosis complex.Cognitive Neurodynamics 09/2011; 5(3):285-91. DOI:10.1007/s11571-011-9165-x · 1.77 Impact Factor