Dopamine Activates Astrocytes in Prefrontal Cortex via α1-Adrenergic Receptors

Abstract

SummaryThe prefrontal cortex (PFC) is a hub for cognitive control, and dopamine profoundly influences its functions. In other brain regions, astrocytes sense diverse neurotransmitters and neuromodulators and, in turn, orchestrate regulation of neuroactive substances. However, basic physiology of PFC astrocytes, including which neuromodulatory signals they respond to and how they contribute to PFC function, is lacking. Here, we characterize divergent signaling signatures in astrocytes of PFC and primary sensory cortex in mice, which are linked to differential responsivity to locomotion. We find that PFC astrocytes express receptors for dopamine, but are unresponsive through the Gs/Gi-cAMP pathway. Instead, fast calcium signals in PFC astrocytes are time-locked to dopamine release, and are mediated by α1-adrenergic receptors both ex vivo and in vivo. Further, we describe dopamine-triggered regulation of extracellular ATP at PFC astrocyte territories. Thus, we identify astrocytes as active players in dopaminergic signaling in PFC, contributing to PFC function though neuromodulator receptor crosstalk.Graphical Abstract

Dopamine-induced astrocytic Ca2+ signaling in mPFC is mediated by MAO-B in young mice, but by dopamine receptors in adult mice

“…Statistical significance is indicated as follows: ***p < 0.001; ****p < 0.0001; ns, not significant. A recent study suggested that mPFC astrocytes were shown to elevate intracellular Ca 2+ in response to DA [21]. To recapitulate the previous finding, we injected the AAV-GfaABC1D-GCaMP6f virus into the mPFC region in young (5 -6 weeks) and adult (> 8 weeks) mice and conducted ex vivo astrocyte Ca 2+ imaging (Fig.…”

“…In contrast to neurons, a recent study reported that DA does not modulate cAMP level of astrocytes [21]. Instead, astrocytes have been shown to elevate their intracellular Ca 2+ in response to DA in vitro [22], ex vivo [16,23], and in vivo [21] in various brain regions. The suggested pathways of DA-mediate astrocytic Ca 2+ signaling are 1) monoamine oxidase B (MAO-B) pathway [22] and 2) DAR pathway [16,21,23].…”

“…In contrast to neurons, a recent study reported that DA does not modulate cAMP level of astrocytes [21]. Instead, astrocytes have been shown to elevate their intracellular Ca 2+ in response to DA in vitro [22], ex vivo [16,23], and in vivo [21] in various brain regions.…”

“…Instead, astrocytes have been shown to elevate their intracellular Ca 2+ in response to DA in vitro [22], ex vivo [16,23], and in vivo [21] in various brain regions. The suggested pathways of DA-mediate astrocytic Ca 2+ signaling are 1) monoamine oxidase B (MAO-B) pathway [22] and 2) DAR pathway [16,21,23]. In the MAO-B pathway, ROS generated during DA metabolism causes lipid peroxidation and phospholipase C (PLC) activation, which induces the IP3R2-mediated Ca 2+ release from the endoplasmic reticulum (ER).…”

Astrocyte-like CEPsh glia respond to stress

“…Recently, astrocytes were also shown to participate in spatial memory formation in mice (Hosli et al,. 2022) and may respond to interior information such as dopamine (Pittolo et al, 2022). The nematode Caenorhabditis elegans (C. elegans) is a good model organism for such studies; it is transparent, allowing live imaging, and its CEPsh cells are well-described astrocyte-like glia (Shaham, 2015).…”