Impaired calcium signaling in astrocytes modulates autism spectrum disorder-like behaviors in mice

Abstract

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder. The mechanisms underlying ASD are unclear. Astrocyte alterations are noted in ASD patients and animal models. However, whether astrocyte dysfunction is causal or consequential to ASD-like phenotypes in mice is unresolved. Type 2 inositol 1,4,5-trisphosphate 6 receptors (IP3R2)-mediated Ca2+ release from intracellular Ca2+ stores results in the activation of astrocytes. Mutations of the IP3R2 gene are associated with ASD. Here, we show that both IP3R2-null mutant mice and astrocyte-specific IP3R2 conditional knockout mice display ASD-like behaviors, such as atypical social interaction and repetitive behavior. Furthermore, we show that astrocyte-derived ATP modulates ASD-like behavior through the P2X2 receptors in the prefrontal cortex and possibly through GABAergic synaptic transmission. These findings identify astrocyte-derived ATP as a potential molecular player in the pathophysiology of ASD.

Astrocytic IP3Rs: Beyond IP3R2

“…Knock-down of IP 3 R1 in dorsal spinal cord astrocytes of IP 3 R2KO mice also unmasked IP 3 R1 mediated Ca 2+ signals (Shiratori-Hayashi et al, 2020). Furthermore, the selective activation of G q -GPCR/IP 3 R/Ca 2+ signaling in astrocytes, using DREADDs (designer receptor exclusively activated by designer drug, see section "Activation of IP 3 Induced Ca 2+ Release in Astrocytes"), triggered Ca 2+ events in the astrocytic processes of IP 3 R2KO mice (Wang et al, 2021) indicating the presence of IP 3 R1/3.…”

“…The three IP 3 R subtypes share only 65-85% homology accounting for many of the subtype-specific properties leading to particular spatiotemporal features of Ca 2+ responses. Although Petravicz et al, 2008;Agulhon et al, 2010;Takata et al, 2011Takata et al, , 2013Navarrete et al, 2012;Tamamushi et al, 2012;Cao et al, 2013;Nizar et al, 2013;Bonder and McCarthy, 2014;Gómez-Gonzalo et al, 2015Mariotti et al, 2016;Monai et al, 2016;Perea et al, 2016;Martin-Fernandez et al, 2017;Sherwood et al, 2017;Tanaka et al, 2017;Wang et al, 2021 (Mataragka and Taylor, 2018). Importantly, IP 3 R channel activity is not only regulated by IP 3 but also by Ca 2+ (Finch et al, 1991).…”

“…Inhibition of IP 3 Induced Ca 2+ Release IP 3 R2KO and conditional-KO (cKO) mice (Petravicz et al, 2014;Padmashri et al, 2015;Wang et al, 2021) are widely used, however, as highlighted above, deletion of IP 3 R2 does not abolish IICR. IICR can be suppressed, irrespective of the underlying receptor, using an IP 3 -sponge to buffer IP 3 (Xie et al, 2010;Tanaka et al, 2013), or an IP 3 -5 -phospatase transgene to enhance IP 3 metabolism (Kanemaru et al, 2007;Foley et al, 2017).…”

Targeting the Oxytocinergic System: A Possible Pharmacological Strategy for the Treatment of Inflammation Occurring in Different Chronic Diseases

“…These results suggest that oxytocin treatment improves autism symptoms in a mouse model of ASD, by ameliorating oxidative stress and inflammation [ 102 , 103 ]. It is important to report that, in different brain regions correlated with ASD, oxytocin receptor-KO mice showed reduced expression of the PSD95 together with a two-fold increase in Iba1; their microglial cells are enlarged and present more branches compared with wild-type animals [ 70 ].…”

P2X Receptor-Dependent Modulation of Mast Cell and Glial Cell Activities in Neuroinflammation

“…P2X2 activation in astrocytes was found to regulate GABAergic transmission and ASD like behaviour in C57BL/6J mice carrying a knockout of the type 2 inositol 1,4,5-trisphosphate 6 receptors (IP3R2) gene, as mutations in this gene are associated with ASD [ 84 ]. Activation of the P2X2 also led to an increase in mRNA expression of leukaemia inhibitory factor (LIF), a cytokine inhibiting cell differentiation, in astrocytes isolated from neonatal C57BL/6J mice.…”