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

<jats:p>Astrocytes in the hippocampus release calcium (Ca<jats:sup>2+</jats:sup>) from intracellular stores intrinsically and in response to activation of G<jats:sub>q</jats:sub>-linked G-protein-coupled receptors (GPCRs) through the binding of inositol 1,4,5-trisphosphate (IP<jats:sub>3</jats:sub>) to its receptor (IP<jats:sub>3</jats:sub>R). Astrocyte Ca<jats:sup>2+</jats:sup>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<jats:sub>3</jats:sub>R type 2 (IP<jats:sub>3</jats:sub>R2) is the primary IP<jats:sub>3</jats:sub>R expressed by astrocytes. To determine whether IP<jats:sub>3</jats:sub>R2 is the primary functional IP<jats:sub>3</jats:sub>R responsible for astrocytic Ca<jats:sup>2+</jats:sup>increases, we conducted experiments using an IP<jats:sub>3</jats:sub>R2 knock-out mouse model (IP<jats:sub>3</jats:sub>R2 KO). We show, for the first time, that lack of IP<jats:sub>3</jats:sub>R2 blocks both spontaneous and G<jats:sub>q</jats:sub>-linked GPCR-mediated increases in astrocyte Ca<jats:sup>2+</jats:sup>. Furthermore, neuronal G<jats:sub>q</jats:sub>-linked GPCR Ca<jats:sup>2+</jats:sup>increases remain intact, suggesting that IP<jats:sub>3</jats:sub>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<jats:sub>3</jats:sub>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<jats:sub>3</jats:sub>R2 KO. These data show that IP<jats:sub>3</jats:sub>R2 is the key functional IP<jats:sub>3</jats:sub>R driving G<jats:sub>q</jats:sub>-linked GPCR-mediated Ca<jats:sup>2+</jats:sup>increases in hippocampal astrocytes and that removal of astrocyte Ca<jats:sup>2+</jats:sup>increases does not significantly affect excitatory neuronal synaptic activity or ambient glutamate levels.</jats:p>