Glia-derived ATP inversely regulates excitability of pyramidal and CCK-positive neurons

Abstract

Astrocyte responds to neuronal activity with calcium waves and modulates synaptic transmission through the release of gliotransmitters. However, little is known about the direct effect of gliotransmitters on the excitability of neuronal networks beyond synapses. Here we show that selective stimulation of astrocytes expressing channelrhodopsin-2 in the CA1 area specifically increases the firing frequency of CCK-positive but not parvalbumin-positive interneurons and decreases the firing rate of pyramidal neurons, phenomena mimicked by exogenously applied ATP. Further evidences indicate that ATP-induced increase and decrease of excitability are caused, respectively, by P2Y1 receptor-mediated inhibition of a two-pore domain potassium channel and A1 receptor-mediated opening of a G-protein-coupled inwardly rectifying potassium channel. Moreover, the activation of ChR2-expressing astrocytes reduces the power of kainate-induced hippocampal ex vivo gamma oscillation. Thus, through distinct receptor subtypes coupled with different K+ channels, astrocyte-derived ATP differentially modulates the excitability of different types of neurons and efficiently controls the activity of neuronal network.

Gi/o protein‐coupled receptors inhibit neurons but activate astrocytes and stimulate gliotransmission

“…In addition to an increase in SIC frequency in nearby neurons, selective astrocyte activation via either G q DREADD or G i/o DREADD signaling led to an increase in action potential firing of hippocampal neurons. While most reports of neuronal‐glial interactions have shown synaptic transmission regulation by astrocytes (Araque et al, ), present results add to recent studies showing that astrocytes can also regulate neuronal firing and network activity (Lee et al, ; Poskanzer & Yuste, , ; Shen, Nikolic, Meunier, Pfrieger, & Audinat, ; Tan et al, ). Indeed, the observed increase in astrocyte Ca 2+ activity upon CNO injection in vivo co‐occurred with an upregulated delta range of the slow‐wave activity.…”

Blocking TNFα‐driven astrocyte purinergic signaling restores normal synaptic activity during epileptogenesis

“…P2Y1 receptors are expressed by astrocytes but also by inhibitory interneurons in the hippocampus (Bowser & Khakh, ; Jourdain et al, ; Pascual et al, ; Tan et al, ). TNFα‐triggered P2Y1 receptor‐dependent Ca 2+ signaling of DG astrocytes is unlikely to be secondary to increased activity of hippocampal interneurons since we have performed experiments in conditions that minimized the influence of neuronal network activity and prevent the activation of GABA A receptors.…”

Corticosterone and serotonin similarly influence GABAergic and purinergic pathways to affect cortical inhibitory networks

“…Astrocytes release gliotransmitters, including ATP, following increases in intracellular calcium levels. ATP is known to depolarise interneurones through P2Y1 receptors to increase the frequency of spontaneous GABA release . Given that 5‐HT‐mediated depolarisation of cortical interneurones also results in a decrease in evoked inhibition by decreasing the action potential amplitude, it is likely that P2Y1‐mediated depolarisation will do the same.…”