Astrocytic IP Rs: Contribution to Ca signalling and hippocampal LTP.

Astrocytes regulate hippocampal synaptic plasticity by the Ca dependent release of the N-methyl d-aspartate receptor (NMDAR) co-agonist d-serine. Previous evidence indicated that d-serine release would be regulated by the intracellular Ca release channel IP receptor (IP R), however, genetic deletion of IP R2, the putative astrocytic IP R subtype, had no impact on synaptic plasticity or transmission. Although IP R2 is widely believed to be the only functional IP R in astrocytes, three IP R subtypes (1, 2, and 3) have been identified in vertebrates. Therefore, to better understand gliotransmission, we investigated the functionality of IP R and the contribution of the three IP R subtypes to Ca signalling. As a proxy for gliotransmission, we found that long-term potentiation (LTP) was impaired by dialyzing astrocytes with the broad IP R blocker heparin, and rescued by exogenous d-serine, indicating that astrocytic IP Rs regulate d-serine release. To explore which IP R subtypes are functional in astrocytes, we used pharmacology and two-photon Ca imaging of hippocampal slices from transgenic mice (IP R2 and IP R2 ;3 ). This approach revealed that underneath IP R2-mediated global Ca events are an overlooked class of IP R-mediated local events, occurring in astroglial processes. Notably, multiple IP Rs were recruited by high frequency stimulation of the Schaffer collaterals, a classical LTP induction protocol. Together, these findings show the dependence of LTP and gliotransmission on Ca release by astrocytic IP Rs. GLIA 2017;65:502-513.