Dopamine-Evoked Synaptic Regulation in the Nucleus Accumbens Requires Astrocyte Activity

Abstract

Dopamine is a key neurotransmitter involved in physiological processes, such as learning and memory, motor control and reward, as well as, pathological conditions, such as Parkinson's disease and drug abuse. In contrast to the extensive studies on neurons, the role of astrocytes in dopaminergic signaling remains largely unknown. Using transgenic mice, optogenetics and pharmacogenetics, we studied the role of astrocytes on the dopaminergic system. We show that in freely-behaving mice, astrocytes in the nucleus accumbens (NAc), a key reward center in the brain, respond with Ca2+ elevations to synaptically-released dopamine, a phenomenon that is enhanced by amphetamine, a psychostimulant drug that acts via increasing dopamine levels. In brain slices, synaptically-released dopamine increases astrocyte Ca2+ and stimulates the release of ATP/adenosine, which leads to excitatory synaptic depression through activation of presynaptic adenosine A1 receptors. Amphetamine depresses neurotransmission through stimulation of astrocytes and the consequent activation of presynaptic A1 receptors. Furthermore, astrocytes modulate the acute behavioral psychomotor effects of amphetamine. Therefore, astrocytes mediate the synaptic regulation induced by dopamine and amphetamine, revealing a novel cellular pathway in the brain reward system.

Astrocytes modulate sensory-evoked neuronal network activity

“…Multiple signaling pathways may be putatively involved in the bidirectional astrocyte-neuron communication underlying the observed results. On the one hand, astrocytes are known to respond with Ca 2+ elevations to a wide variety of neurotransmitters released at cortical synapses active during the sensory stimulation, including glutamate, GABA, acetylcholine, norepinephrine or dopamine 9 , 11 , 42 , 43 . On the other hand, multiple astrocyte signaling mechanisms may influence neuronal activity 9 , 11 , 44 , either through synapse-specific or volume transmission 45 – 47 .…”

Radial glia in the zebrafish brain: Functional, structural, and physiological comparison with the mammalian glia

“…Recent evidences highlight important roles of astroglia in regulating neural activity, brain states, and animal behavior, both in vertebrates (Brancaccio, Patton, Chesham, Maywood, & Hastings, 2017) and invertebrates (Ma, Stork, Bergles, & Freeman, 2016). Studies in rodents showed that astroglial cells are highly dynamic components of the brain, which respond to locomotion (Nimmerjahn, Mukamel, & Schnitzer, 2009; Sekiguchi et al, 2016; Slezak et al, 2019) or sensory stimulation (Gu et al, 2018; Slezak et al, 2019) with prominent changes in astroglial calcium levels and can regulate learning (Adamsky et al, 2018; Corkrum et al, 2020) or other state transitions (Bojarskaite et al, 2019; Cui et al, 2018; Oe et al, 2020; Poskanzer & Yuste, 2016) in the brain. Norepinephrine (Bekar, He, & Nedergaard, 2008; Oe et al, 2020; Salm & McCarthy, 1990; Shao & McCarthy, 1997) and acetylcholine (Araque, Martin, Perea, Arellano, & Buno, 2002; Pabst et al, 2016; Takata et al, 2011) are proposed to be the primary triggers for activating astroglia, yet several other molecules including glutamate (Hamilton et al, 2008; Mothet et al, 2005; Sun et al, 2013) play prominent roles in astroglial physiology.…”

Regulation of GluA1 phosphorylation by d‐amphetamine and methylphenidate in the cerebellum

“…Such regulatory mechanism is functionally important because it contributes to the modulation of both excitatory synaptic transmission and acute hyperlocomotor effects of d-amphetamine. 52 Although D1Rs expressed in BGCs do not participate to the regulation of GluA1 phosphorylation, their potential role in the regulation of BGCs Ca 2+ signaling will require further investigation.…”