Astrocytic IP₃Rs: Contribution to Ca²⁺ signalling and hippocampal LTP

Abstract

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.

Synapse-specific astrocyte gating of amygdala-related behavior

“…1h,l), which largely mediates G-protein-mediated calcium elevation in astrocytes, thus suggesting that synaptic regulation requires the elevation of calcium levels in astrocytes. Because other types of IP 3 receptors have recently been shown to contribute to astrocyte calcium mobilization 43 , we further tested the astrocytic calcium dependency by loading astrocytes with the calcium chelator BAPTA, by whole-cell patch-clamping astrocytes with a solution containing 40 mM BAPTA. Astrocytes are known to be gap-junction coupled in different brain areas, which allows the diffusion of BAPTA in the astrocytic network from single recorded astrocytes 44, 45 .…”

Human astrocytes: structure and functions in the healthy brain

“…KO studies have suggested that, first, it modulates mainly somatic Ca 2+ transients (Srinivasan et al 2015), and second, that it does not regulate neuronal excitability, synaptic transmission and plasticity, neurovascular coupling or behaviour (Petravicz et al 2008, 2014; Agulhon et al 2010; Nizar et al 2013; Bonder and McCarthy 2014). Alternative mechanisms to induce Ca 2+ rises have been proposed, such as other IP3Rs or transient receptor potential cation channels A1 (TRPA1) (Shigetomi et al 2011; Sherwood et al 2017). As discussed, the emerging view that Ca 2+ signalling might be compartmentalised suggests that Ca 2+ elevations may be triggered through different pathways in the soma, branches and processes (Bazargani and Attwell 2016).…”

Investigating brain d‐serine: Advocacy for good practices

“…65 Based on previous findings precisely demonstrating in vitro that glia may release D-serine through a Ca 2+regulated process, 66,67 it was claimed that astrocytic IP3 receptors contribute to the astrocyte release of D-serine thereby controlling functional plasticity at synapses. 65 Based on previous findings precisely demonstrating in vitro that glia may release D-serine through a Ca 2+regulated process, 66,67 it was claimed that astrocytic IP3 receptors contribute to the astrocyte release of D-serine thereby controlling functional plasticity at synapses.…”