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The Journal of Neuroscience, May 7, 2008, 28(19):4967-4973; doi:10.1523/JNEUROSCI.5572-07.2008

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

Jeremy Petravicz,¹ Todd A. Fiacco,² and Ken D. McCarthy^1,2

¹Curriculum in Neurobiology and ²Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599

Correspondence should be addressed to Jeremy Petravicz, Curriculum in Neurobiology, University of North Carolina at Chapel Hill, Campus Box #7320, Chapel Hill, NC 27599-7320. Email: jeremy_petravicz{at}med.unc.edu

Astrocytes in the hippocampus release calcium (Ca²⁺) 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 (IP₃) to its receptor (IP₃R). Astrocyte Ca²⁺ 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 IP₃R type 2 (IP₃R2) is the primary IP₃R expressed by astrocytes. To determine whether IP₃R2 is the primary functional IP₃R responsible for astrocytic Ca²⁺ increases, we conducted experiments using an IP₃R2 knock-out mouse model (IP₃R2 KO). We show, for the first time, that lack of IP₃R2 blocks both spontaneous and G_q-linked GPCR-mediated increases in astrocyte Ca²⁺. Furthermore, neuronal G_q-linked GPCR Ca²⁺ increases remain intact, suggesting that IP₃R2 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 IP₃R2 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 IP₃R2 KO. These data show that IP₃R2 is the key functional IP₃R driving G_q-linked GPCR-mediated Ca²⁺ increases in hippocampal astrocytes and that removal of astrocyte Ca²⁺ increases does not significantly affect excitatory neuronal synaptic activity or ambient glutamate levels.

Key words: astrocyte; calcium; inositol 1,4,5-trisphosphate; IP₃ receptor; hippocampus; gliotransmitter

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Received Dec. 17, 2007; revised April 2, 2008; accepted April 6, 2008.

Correspondence should be addressed to Jeremy Petravicz, Curriculum in Neurobiology, University of North Carolina at Chapel Hill, Campus Box #7320, Chapel Hill, NC 27599-7320. Email: jeremy_petravicz{at}med.unc.edu

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