Astrocytic IP₃Rs: Contribution to Cap>2+p> signalling and hippocampal LTP

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• 作者：Mark William Sherwood ; Misa Arizono ; Chihiro Hisatsune ; Hiroko Bannai ; Etsuko Ebisui ; John Lawrence Sherwood ; Aude Panatier ; St&eacute ; phane Henri Richard Oliet and Katsuhiko Mikoshiba
• 刊名：Glia
• 出版年：2017
• 出版时间：March 2017
• 年：2017
• 卷：65
• 期：3
• 页码：502-513
• 全文大小：939K
• ISSN：1098-1136

文摘

Astrocytes regulate hippocampal synaptic plasticity by the Cap>2+p> dependent release of the N-methyl pan class="smallCaps">dpan>-aspartate receptor (NMDAR) co-agonist pan class="smallCaps">dpan>-serine. Previous evidence indicated that pan class="smallCaps">dpan>-serine release would be regulated by the intracellular Cap>2+p> release channel IP₃ receptor (IP₃R), however, genetic deletion of IP₃R2, the putative astrocytic IP₃R subtype, had no impact on synaptic plasticity or transmission. Although IP₃R2 is widely believed to be the only functional IP₃R in astrocytes, three IP₃R subtypes (1, 2, and 3) have been identified in vertebrates. Therefore, to better understand gliotransmission, we investigated the functionality of IP₃R and the contribution of the three IP₃R subtypes to Cap>2+p> signalling. As a proxy for gliotransmission, we found that long-term potentiation (LTP) was impaired by dialyzing astrocytes with the broad IP₃R blocker heparin, and rescued by exogenous pan class="smallCaps">dpan>-serine, indicating that astrocytic IP₃Rs regulate pan class="smallCaps">dpan>-serine release. To explore which IP₃R subtypes are functional in astrocytes, we used pharmacology and two-photon Cap>2+p> imaging of hippocampal slices from transgenic mice (IP₃R2p>−/−p> and IP₃R2p>−/−p>;3p>−/−p>). This approach revealed that underneath IP₃R2-mediated global Cap>2+p> events are an overlooked class of IP₃R-mediated local events, occurring in astroglial processes. Notably, multiple IP₃Rs 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 Cap>2+p> release by astrocytic IP₃Rs. GLIA 2017;65:502–513