Disentangling the Role of Astrocytes in Alcohol Use Disorder

Abstract

Several laboratories recently identified that astrocytes are critical regulators of addiction machinery. It is now known that astrocyte pathology is a common feature of ethanol (EtOH) exposure in both humans and animal models, as even brief EtOH exposure is sufficient to elicit long-lasting perturbations in astrocyte gene expression, activity, and proliferation. Astrocytes were also recently shown to modulate the motivational properties of EtOH and other strongly reinforcing stimuli. Given the role of astrocytes in regulating glutamate homeostasis, a crucial component of alcohol use disorder (AUD), astrocytes might be an important target for the development of next-generation alcoholism treatments. This review will outline some of the more prominent features displayed by astrocytes, how these properties are influenced by acute and long-term EtOH exposure, and future directions that may help to disentangle astrocytic from neuronal functions in the etiology of AUD.

Keywords: Alcohol Use Disorder; Astrocyte; Gliotransmission; Glutamate.

Figure 1. Glial cells provide metabolic support while buffering the extracellular milieu

The glia cell family is pivotal for neuronal function, and astrocytes are the most numerous glial cells in mammalian brain. By enseathing blood vessels, astrocytes can serve as a conduit for delivery of energetic metabolites to distal neurons during energy consuming processes in addition to buffering excess central nervous system ions and small molecules. In the mature brain, oligodendrocytes increase conduction velocity of larger nerve fibers by enseathing axons between nodes of Ranvier. Microglia, and to a limited extent astrocytes, provide innate immune responses. Arrows represents the flow of nutrients that is taken up by astrocytes from the blood vessels, and transported to surrounding cells.

Figure 2. Astrocytes control excitatory neurotransmission

Astrocytes regulate glutamatergic signaling on multiple levels. Not only are astrocytes primarily responsible for clearing glutamate in the brain, they also take up glycine, which is a co-agonist for the NMDA receptor. In addition, astrocytes release gliotransmitters such as D-serine and glutamate, which could further influence excitatory transmission especially at ionotropic NMDA receptors. See text for further details. Glu=glutamate, Gln=glutamine, mGluR=metabotropic glutamate receptors, AMPA/NMDA=ionotropic glutamate receptors, ADP=adenosine diphosphate.

Figure 3. Receptor activated calcium signaling in astrocytes

Astrocytic calcium transients are primarily mediated through the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol (1,4,5) trisphosphate (IP3) following activation of G-protein coupled receptors. IP3 promotes the release of Ca2+ predominately from intracellular pools (endoplasmatic reticulum; ER), into the cytoplasm, and influx of calcium through calcium channels primarily activated by changes in membrane potential. Following formation/release of IP3 or Ca2+, these signaling molecules may spread to surrounding astrocytes through gap junction channels (Gjc) and lead to coordinated release of gliotransmitters.

Figure 4. Pathway specific integration of synaptic information

Astrocytes are important information processors in the neural network, and astrocytes may support and regulate neurotransmission in a pathway specific manner (for instance interacting with synapse 1 and 2 but not 3). Neuronal activity evokes complex intrinsic changes in intracellular Ca2+ that may spread through the astrocytic network, and provoke the release of gliotransmitters at distal synapses. One astrocyte may be in contact with thousands of synapses, enabling synaptic interaction without direct neuronal connectivity, as shown between synapse 1 and 2. See text for further details. Gjc=gap junction coupling.

Figure 5. Immune signaling during ethanol exposure

Simplified schematic showing how ethanol exposure can promote signaling via Toll like receptors (TLRs), leading to activation of nuclear factor kappa B (NF-κB), secretion of pro-inflammatory cytokines and chemokines, and elevated levels of Reactive Oxygen Species (ROS). See text for further details.

Figure 6. Ethanol-mediated disruption of the balance between excitation and inhibition

Ethanol can perturb excitatory balance by altering astrocyte calcium signaling and the clearance of neurotransmitters. Ethanol modulates receptor-mediated responses in a pathway specific manner, and may directly increase Ca²⁺ signaling in a subset of astrocytes. Ethanol also suppresses adenosine-uptake via the astrocytic equilibrative nucleoside transporter 1 (ENT1), leading to increased levels of adenosine and activation of purinergic receptors (A1AR, A2AR, P2XR) resulting in indirect modulation of glutamate and GABA clearence. MR=muscarinic receptor, 5-HTR=serotonin receptor. See text for further details.

Figure 7. Ethanol-induced cell swelling

A subset of astrocytes responds to ethanol exposure with an increase in cell volume, which can lead to crowding of molecules in the extracellular space, changes in volume transmission and possibly neurotoxicity. In addition, ethanol-induced cell swelling may lead to impaired communication through gap junction channels, reduced clearance of neuroactive substances and decreased glucose transport (illustrated with white x-marks) (Abdul Muneer et al., 2011), thereby indirectly affecting neurotransmission. Importantly, cell swelling can also promote the release of taurine, which appears to play a key role in the dopamine-elevating properties of ethanol. See text for further details. AQ4=aquaporin-4.