Loss of IP3Receptor-Dependent Ca2+Increases in Hippocampal Astrocytes Does Not Affect Baseline CA1 Pyramidal Neuron Synaptic Activity

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Abstract
Astrocytes in the hippocampus release calcium (Ca2+) from intracellular stores intrinsically and in response to activation of Gq-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 Gq-linked GPCR-mediated increases in astrocyte Ca2+. Furthermore, neuronal Gq-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 Gq-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.