Bidirectional regulation by “star forces”: Ionotropic astrocyte's optical stimulation suppresses synaptic plasticity, metabotropic one strikes back

Abstract

The role of astrocytes in modulating synaptic plasticity is an important question that until recently was not addressed due to limitations of previously existing technology.In the present study, we took an advantage of optogenetics to specifically activate astrocytes in hippocampal slices in order to study effects on synaptic function. Using the AAV-based delivery strategy, we expressed the ionotropic channelrhodopsin-2 (ChR2) or the metabotropic Gq-coupled Opto-a1AR opsins specifically in hippocampal astrocytes to compare different modalities of astrocyte activation. In electrophysiological experiments, we observed a depression of basal field excitatory postsynaptic potentials (fEPSPs) in the CA1 hippocampal layer following light stimulation of astrocytic ChR2. The ChR2-mediated depression increased under simultaneous light and electrical theta-burst stimulation (TBS). Application of the type 2 purinergic receptor antagonist suramin prevented depression of basal synaptic transmission, and switched the ChR2-dependent depression into potentiation. The GABA B receptor antagonist, phaclofen, did not prevent the depression of basal fEPSPs, but switched the ChR2-dependent depression into potentiation comparable to the values for TBS in control slices. In contrast, light stimulation of Opto-a1AR expressed in astrocytes led to an increase in basal fEPSPs, as well as a potentiation of synaptic responses to TBS significantly. A specific blocker of the Gq protein downstream target, the phospholipase C, U73122, completely prevented the effects of Opto-a1AR stimulation on basal fEPSPs or Opto + TBS responses. To understand molecular basis for the observed effects, we performed an analysis of gene expression in these slices using quantitative PCR approach. We observed a significant upregulation of "immediate-early" gene expression in hippocampal slices after light activation of Opto-a1ARexpressing astrocytes alone (cRel, Arc, Fos, JunB, and Egr1) or paired with TBS (cRel, Fos, and Egr1). Activation of ChR2-expressing hippocampal astrocytes was insufficient to affect expression of these genes in our experimental conditions. Thus, we concluded that optostimulation of astrocytes with ChR2 and Opto-a1AR optogenetic

Astrocyte‐ and NMDA receptor‐dependent slow inward currents differently contribute to synaptic plasticity in an age‐dependent manner in mouse and human neocortex

“…Astrocytic activity induced LTP in the mouse hippocampus which contributes to learning and memory recall (Adamsky et al, 2018 ). On the murine hippocampus, optogenetic astrocyte activation elicited LTD alone via ChR2 and it elicited LTP via Opto‐a1AR (Maltsev et al, 2023 ). In the mouse striatum, astrocytic activation and adenosin release elicits LTD by solely astrocytic activation.…”

“…On the murine hippocampus, optogenetic astrocyte activation elicited LTD alone via ChR2 and it elicited LTP via Opto-a1AR (Maltsev et al, 2023). In the mouse striatum, astrocytic activation and adenosin release elicits LTD by solely astrocytic activation.…”

Activation of Gq-Coupled Receptors in Astrocytes Restores Cognitive Function in Alzheimer’s Disease Mice Model

“…Previously, we determined that the stimulation of astrocytes expressing the OptoGq metabotropic construct led to an increase in the number of spontaneous excitatory postsynaptic currents (sEPSC) in the pyramidal neurons of the hippocampus, as well as to the potentiation of the fEPSP values in the acute brain slices of the hippocampus [ 5 ]. Moreover, the activation of Gq-coupled receptors in astrocytes enhanced early immediate gene expression [ 36 ]. Based on this evidence, the current study showed the effect of optogenetic stimulation of the metabotropic opsin OPTO-α1AR expressed in astrocytes on the formation of long-term potentiation in mice with the genetic model of Alzheimer’s disease known as 5xFAD.…”

“…One of the ways of precisely controlling or modulating astrocyte activity is the optogenetic method [5,[34][35][36]. This allows scientists to regulate the activity of different cells through genetically constructed photosensitive channels-opsins [37][38][39][40][41].…”

“…In the current study, optogenetic modulation of astrocytic activity was performed via metabotropic OPTO-α1AR, the activation of which led to Gq pathway involvement [ 42 ]. We have shown earlier that the influence of the optogenetic activation of OPTO-α1AR, expressed in the hippocampal astrocytes, resulted in the elevation of neuronal activity, facilitation of fEPSP values in the hippocampal area and expression elevation of genes encoding various transcriptional factors [ 5 , 36 ]. In this study, the effect of the optogenetic modulation of astrocytes on long-term potentiation, mushroom spine density and fear conditioning test is shown in transgenic mice model of Alzheimer’s disease 5xFAD.…”