Astrocytic IP 3 Rs: Contribution to Ca 2+ signalling and hippocampal LTP

Astrocytes regulate hippocampal synaptic plasticity by the Ca 2+ 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 2+ release channel IP 3 receptor (IP 3 R), however, genetic deletion of IP 3 R2, the putative astrocytic IP 3 R subtype, had no impact on synaptic plasticity or transmission. Although IP 3 R2 is widely believed to be the only functional IP 3 R in astrocytes, three IP 3 R subtypes (1, 2, and 3) have been identified in vertebrates. Therefore, to better understand gliotransmission, we investigated the functionality of IP 3 R and the contribution of the three IP 3 R subtypes to Ca 2+ signalling. As a proxy for gliotransmission, we found that long‐term potentiation (LTP) was impaired by dialyzing astrocytes with the broad IP 3 R blocker heparin, and rescued by exogenous d ‐serine, indicating that astrocytic IP 3 Rs regulate d ‐serine release. To explore which IP 3 R subtypes are functional in astrocytes, we used pharmacology and two‐photon Ca 2+ imaging of hippocampal slices from transgenic mice (IP 3 R2 −/− and IP 3 R2 −/− ;3 −/− ). This approach revealed that underneath IP 3 R2‐mediated global Ca 2+ events are an overlooked class of IP 3 R‐mediated local events, occurring in astroglial processes. Notably, multiple IP 3 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 2+ release by astrocytic IP 3 Rs. GLIA 2017;65:502–513