Neurotransmitter signaling in the pathophysiology of microglia

Abstract

Microglial cells are the resident immune cells of the central nervous system. In the resting state, microglia are highly dynamic and control the environment by rapidly extending and retracting motile processes. Microglia are closely associated with astrocytes and neurons, particularly at the synapses, and more recent data indicate that neurotransmission plays a role in regulating the morphology and function of surveying/resting microglia, as they are endowed with receptors for most known neurotransmitters. In particular, microglia express receptors for ATP and glutamate, which regulate microglial motility. After local damage, the release of ATP induces microgliosis and activated microglial cells migrate to the site of injury, proliferate, and phagocytose cells, and cellular compartments. However, excessive activation of microglia could contribute to the progression of chronic neurodegenerative diseases, though the underlying mechanisms are still unclear. Microglia have the capacity to release a large number of substances that can be detrimental to the surrounding neurons, including glutamate, ATP, and reactive oxygen species. However, how altered neurotransmission following acute insults or chronic neurodegenerative conditions modulates microglial functions is still poorly understood. This review summarizes the relevant data regarding the role of neurotransmitter receptors in microglial physiology and pathology.

Keywords: ATP; glutamate; microglia; purinergic and glutamatergic receptors.

Figure 1

Purinergic signaling in microglia. Release or leakage of nucleotides/nucleosides from injured neurons, astrocytes, or microglial cells induces phenotypic alterations in microglia. Microglial processes exhibit constitutive motility, which is dependent on ATP signaling. Microglial processes are rapidly recruited to sites of CNS tissue damage by P2Y12 and A₃ receptor activation. As the damage progresses, microglia undergo progressive changes, including altered expression of cell surface markers and inflammation-related genes, process retraction and the acquisition of an ameboid morphology, cell body migration, and increasing phagocytic ability. The changes in microglial functions are partly associated with changes in purinergic receptors that determine different responses to ATP. Thus, process retraction is mainly due to upregulation of A_2A and downregulation of P2Y12 receptors, whereas migration is mediated by A₁ and P2X4 receptors and proliferation by P2X7 receptors. Phagocytosis signaling is also unmasked by the upregulation of P2Y6, which is activated by the release of UTP by dying cells. See also Table 1.

Figure 2

Activated microglia can kill oligodendrocytes via a dual mechanism leading to glutamate excitotoxicity. Microglia release glutamate, primarily through the cystine/glutamate exchange system (system x⁻_c), which is highly active in these cells due to its high rate of reactive oxygen species (ROS) production. Thus, cystine is intracellularly converted into cysteine, the rate-limiting substrate in glutathione synthesis. Under physiological conditions, glutamate released by the exchanger is efficiently taken up by glutamate transporters expressed in surrounding cells, including astrocytes and oligodendrocytes. In contrast, microglia activated by pro-inflammatory stimuli (e.g., LPS acting at TLR4) release ROS and pro-inflammatory cytokines that impair the function of glutamate transporters, such as TNF-α and IL-1β, elevating extracellular glutamate levels. In addition, the over-expression of system x⁻_c in activated microglia increases ambient glutamate concentrations. Together, these deleterious effects on glutamate homeostasis can result in excitotoxicity (Domercq et al., 2007). CySS, cystine; Glu, glutamate; LPS, lipopolysaccharide; TLR4, Toll-like receptor.