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Glia ; 65(3): 502-513, 2017 03.
Article in English | MEDLINE | ID: mdl-28063222

ABSTRACT

Astrocytes regulate hippocampal synaptic plasticity by the Ca2+ 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 Ca2+ release channel IP3 receptor (IP3 R), however, genetic deletion of IP3 R2, the putative astrocytic IP3 R subtype, had no impact on synaptic plasticity or transmission. Although IP3 R2 is widely believed to be the only functional IP3 R in astrocytes, three IP3 R subtypes (1, 2, and 3) have been identified in vertebrates. Therefore, to better understand gliotransmission, we investigated the functionality of IP3 R and the contribution of the three IP3 R subtypes to Ca2+ signalling. As a proxy for gliotransmission, we found that long-term potentiation (LTP) was impaired by dialyzing astrocytes with the broad IP3 R blocker heparin, and rescued by exogenous d-serine, indicating that astrocytic IP3 Rs regulate d-serine release. To explore which IP3 R subtypes are functional in astrocytes, we used pharmacology and two-photon Ca2+ imaging of hippocampal slices from transgenic mice (IP3 R2-/- and IP3 R2-/- ;3-/- ). This approach revealed that underneath IP3 R2-mediated global Ca2+ events are an overlooked class of IP3 R-mediated local events, occurring in astroglial processes. Notably, multiple IP3 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 Ca2+ release by astrocytic IP3 Rs. GLIA 2017;65:502-513.


Subject(s)
Astrocytes/metabolism , Calcium Signaling/physiology , Hippocampus/cytology , Inositol 1,4,5-Trisphosphate Receptors/metabolism , Long-Term Potentiation/physiology , Age Factors , Animals , Animals, Newborn , Calcium-Binding Proteins/genetics , Calcium-Binding Proteins/metabolism , Electric Stimulation , In Vitro Techniques , Inositol 1,4,5-Trisphosphate Receptors/genetics , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Methoxyhydroxyphenylglycol/analogs & derivatives , Methoxyhydroxyphenylglycol/pharmacology , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Confocal , Organ Culture Techniques , Patch-Clamp Techniques , Transfection
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