Loss of IP3 Receptor-Dependent Ca2+ Increases in Hippocampal Astrocytes Does Not Affect Baseline CA1 Pyramidal Neuron Synaptic Activity

Curriculum in Neurobiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 06/2008; 28(19):4967-73. DOI: 10.1523/JNEUROSCI.5572-07.2008
Source: PubMed

ABSTRACT Astrocytes in the hippocampus release calcium (Ca(2+)) from intracellular stores intrinsically and in response to activation of G(q)-linked G-protein-coupled receptors (GPCRs) through the binding of inositol 1,4,5-trisphosphate (IP(3)) to its receptor (IP(3)R). Astrocyte Ca(2+) has been deemed necessary and sufficient to trigger the release of gliotransmitters, such as ATP and glutamate, from astrocytes to modulate neuronal activity. Several lines of evidence suggest that IP(3)R type 2 (IP(3)R2) is the primary IP(3)R expressed by astrocytes. To determine whether IP(3)R2 is the primary functional IP(3)R responsible for astrocytic Ca(2+) increases, we conducted experiments using an IP(3)R2 knock-out mouse model (IP(3)R2 KO). We show, for the first time, that lack of IP(3)R2 blocks both spontaneous and G(q)-linked GPCR-mediated increases in astrocyte Ca(2+). Furthermore, neuronal G(q)-linked GPCR Ca(2+) increases remain intact, suggesting that IP(3)R2 does not play a major functional role in neuronal calcium store release or may not be expressed in neurons. Additionally, we show that lack of IP(3)R2 in the hippocampus does not affect baseline excitatory neuronal synaptic activity as measured by spontaneous EPSC recordings from CA1 pyramidal neurons. Whole-cell recordings of the tonic NMDA receptor-mediated current indicates that ambient glutamate levels are also unaffected in the IP(3)R2 KO. These data show that IP(3)R2 is the key functional IP(3)R driving G(q)-linked GPCR-mediated Ca(2+) increases in hippocampal astrocytes and that removal of astrocyte Ca(2+) increases does not significantly affect excitatory neuronal synaptic activity or ambient glutamate levels.

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Available from: Todd A Fiacco, Sep 28, 2015
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    • "The activation of IP 3 R2 in astrocytes is primarily responsible for increases in astrocyte Ca 2+ [5] [18], although the involvement of other mechanisms in generation of Ca 2+ signals have recently been shown [10, 46–48]. We find that mIP 3 R2 mice exhibit a mild learning impairment in the motor-skill learning task that is consistent with only a partial loss of IP 3 R2-dependent Ca 2+ signaling in these mice. "
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    ABSTRACT: Motor-skill learning induces changes in synaptic structure and function in the primary motor cortex through the involvement of a long-term potentiation- (LTP-) like mechanism. Although there is evidence that calcium-dependent release of gliotransmitters by astrocytes plays an important role in synaptic transmission and plasticity, the role of astrocytes in motor-skill learning is not known. To test the hypothesis that astrocytic activity is necessary for motor-skill learning, we perturbed astrocytic function using pharmacological and genetic approaches. We find that perturbation of astrocytes either by selectively attenuating IP3R2 mediated astrocyte Ca(2+) signaling or using an astrocyte specific metabolic inhibitor fluorocitrate (FC) results in impaired motor-skill learning of a forelimb reaching-task in mice. Moreover, the learning impairment caused by blocking astrocytic activity using FC was rescued by administration of the gliotransmitter D-serine. The learning impairments are likely caused by impaired LTP as FC blocked LTP in slices and prevented motor-skill training-induced increases in synaptic AMPA-type glutamate receptor in vivo. These results support the conclusion that normal astrocytic Ca(2+) signaling during a reaching task is necessary for motor-skill learning.
    Neural Plasticity 09/2015; 2015:938023. DOI:10.1155/2015/938023 · 3.58 Impact Factor
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    • "in and Nevian , 2012 ; Navarrete et al . , 2012 ; Parri et al . , 2001 ; Perea and Araque , 2007 ) . This does not necessarily imply that elegant experimental manipu - lations with astroglial Ca 21 within a certain dynamic range by triggering certain cellular cascades should reproduce such effects ( Agulhon et al . , 2010 ; Fiacco et al . , 2007 ; Petravicz et al . , 2008 ) ( see ( Rusakov et al . , 2014 ; Volterra et al . , 2014 ) for discussion ) . In addition to the much debated astrocyte - neuron exchange , Ca 21 rises in astrocytes could also boost the expression level of glutamate transporters ( Devaraju et al . , 2013 ) , re - position mitochondria closer to glutamate trans - porters ( Jackson et "
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    ABSTRACT: Memory formation in the brain is thought to rely on the remodeling of synaptic connections which eventually results in neural network rewiring. This remodeling is likely to involve ultrathin astroglial protrusions which often occur in the immediate vicinity of excitatory synapses. The phenomenology, cellular mechanisms, and causal relationships of such astroglial restructuring remain, however, poorly understood. This is in large part because monitoring and probing of the underpinning molecular machinery on the scale of nanoscopic astroglial compartments remains a challenge. Here we briefly summarize the current knowledge regarding the cellular organisation of astroglia in the synaptic microenvironment and discuss molecular mechanisms potentially involved in use-dependent astroglial morphogenesis. We also discuss recent observations concerning morphological astroglial plasticity, the respective monitoring methods, and some of the newly emerging techniques that might help with conceptual advances in the area. GLIA 2015. © 2015 The Authors. Glia Published by Wiley Periodicals, Inc.
    Glia 03/2015; DOI:10.1002/glia.22821 · 6.03 Impact Factor
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    • "Ca 2+ signaling in astrocytes has been linked to diverse phenomena, including changes in blood vessel diameter (Attwell et al., 2010; Mulligan and MacVicar, 2004) and synaptic plasticity (Di Castro et al., 2011; Min and Nevian, 2012; Jourdain et al., 2007), suggesting that the impact of astrocytes on various aspects of brain physiology is controlled by these metabotropic receptors. Nevertheless, the role of Ca 2+ signaling in astrocytes in vivo remains uncertain, and mice that lack IP3R2 Ca 2+ release channels that are responsible for receptor-evoked Ca 2+ transients are overtly normal (Petravicz et al., 2008). Our lack of understanding about the interaction of astrocytes with neural circuits reflects our limited knowledge about the behavioral contexts in which astrocyte networks are activated. "
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    ABSTRACT: Astrocytes perform crucial supportive functions, including neurotransmitter clearance, ion buffering, and metabolite delivery. They can also influence blood flow and neuronal activity by releasing gliotransmitters in response to intracellular Ca(2+) transients. However, little is known about how astrocytes are engaged during different behaviors in vivo. Here we demonstrate that norepinephrine primes astrocytes to detect changes in cortical network activity. We show in mice that locomotion triggers simultaneous activation of astrocyte networks in multiple brain regions. This global stimulation of astrocytes was inhibited by alpha-adrenoceptor antagonists and abolished by depletion of norepinephrine from the brain. Although astrocytes in visual cortex of awake mice were rarely engaged when neurons were activated by light stimulation alone, pairing norepinephrine release with light stimulation markedly enhanced astrocyte Ca(2+) signaling. Our findings indicate that norepinephrine shifts the gain of astrocyte networks according to behavioral state, enabling astrocytes to respond to local changes in neuronal activity.
    Neuron 06/2014; 82(6):1263-1270. DOI:10.1016/j.neuron.2014.04.038 · 15.05 Impact Factor
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