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.

Glioblastoma cells induce differential glutamatergic gene expressions in human tumor-associated microglia/macrophages and monocyte-derived macrophages

“…Glutamate has also been shown to work as a chemoattractant for microglia via AMPA and metabotropic glutamate receptors. 31,32 Therefore, glutamate released by tumor cells may trigger the GluA2-mediated chemotaxis of resident microglia toward the tumor site.…”

The L-type voltage-gated calcium channel modulates microglial pro-inflammatory activity

“…As a response to signals released during injury, this microglial transition from a surveillance state towards a more reactive one represents an important phenotypic change (Colton and Wilcock, 2010;Domercq et al, 2013;Kettenmann et al, 2011). As a result, reactive microglia releases pro-inflammatory cytokines and neurotoxic factors, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and reactive oxygen species, the excessive production of which may trigger or exacerbate neuronal death (Liao et al, 2012;Zhang et al, 2011).…”

Neurotransmitter signaling in white matter

“…In contrast, little is known about glutamate receptors in WM microglia, although glutamate is involved in the transmission of death signals to microglia, to which they respond by migrating to sites of neuronal injury (Sieger et al, 2012). In GM, ramified microglia may express AMPA and mGluR which can promote inflammation, chemotaxis, neuroprotection or neurotoxicity (for reviews see Domercq et al, 2013;Pocock and Kettenmann, 2007). …”