期刊
MOLECULAR BRAIN
卷 14, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13041-021-00856-w
关键词
Astrocytes; Chemogenetics; DREADDs; Calcium imaging; Long-term potentiation; LTP; Hippocampus; Schaffer collateral
资金
- King Baudouin Foundation
- Platform for Education and Talent
- FWO
- Fund for Scientific Research Flanders (FWO) [1140619N]
- Wetenschappelijk Fonds Willy Gepts of the UZ Brussel
- Vrije Universiteit Brussel [SRP49]
Astrocytes express a variety of GPCRs crucial for synaptic activity regulation. Activation of these receptors can lead to changes in intracellular Ca2+ levels, gliotransmitter release, and bidirectional neuron-astrocyte communication. Designer receptors exclusively activated by designer drugs (DREADDs) have been instrumental in uncovering the roles of astrocytes in both normal and pathological conditions. They offer a specific way to target astrocytic signaling pathways, although discrepancies in research findings still exist.
Astrocytes express a plethora of G protein-coupled receptors (GPCRs) that are crucial for shaping synaptic activity. Upon GPCR activation, astrocytes can respond with transient variations in intracellular Ca2+. In addition, Ca2+-dependent and/or Ca2+-independent release of gliotransmitters can occur, allowing them to engage in bidirectional neuron-astrocyte communication. The development of designer receptors exclusively activated by designer drugs (DREADDs) has facilitated many new discoveries on the roles of astrocytes in both physiological and pathological conditions. They are an excellent tool, as they can target endogenous GPCR-mediated intracellular signal transduction pathways specifically in astrocytes. With increasing interest and accumulating research on this topic, several discrepancies on astrocytic Ca2+ signalling and astrocyte-mediated effects on synaptic plasticity have emerged, preventing a clear-cut consensus about the downstream effects of DREADDs in astrocytes. In the present study, we performed a side-by-side evaluation of the effects of bath application of the DREADD agonist, clozapine-N-oxide (10 mu M), on Gq- and Gi-DREADD activation in mouse CA1 hippocampal astrocytes. In doing so, we aimed to avoid confounding factors, such as differences in experimental procedures, and to directly compare the actions of both DREADDs on astrocytic intracellular Ca2+ dynamics and synaptic plasticity in acute hippocampal slices. We used an adeno-associated viral vector approach to transduce dorsal hippocampi of male, 8-week-old C57BL6/J mice, to drive expression of either the Gq-DREADD or Gi-DREADD in CA1 astrocytes. A viral vector lacking the DREADD construct was used to generate controls. Here, we show that agonism of Gq-DREADDs, but not Gi-DREADDs, induced consistent increases in spontaneous astrocytic Ca2+ events. Moreover, we demonstrate that both Gq-DREADD as well as Gi-DREADD-mediated activation of CA1 astrocytes induces long-lasting synaptic potentiation in the hippocampal CA1 Schaffer collateral pathway in the absence of a high frequency stimulus. Moreover, we report for the first time that astrocytic Gi-DREADD activation is sufficient to elicit de novo potentiation. Our data demonstrate that activation of either Gq or Gi pathways drives synaptic potentiation through Ca2+-dependent and Ca2+-independent mechanisms, respectively.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据