Abstract
Glia form a central component of the nervous system whose varied activities sustain an environment that is optimised for healthy development and neuronal function. Alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA)-type glutamate receptors (AMPAR) are a central mediator of glutamatergic excitatory synaptic transmission, yet they are also expressed in a wide range of glial cells where they influence a variety of important cellular functions. AMPAR enable glial cells to sense the activity of neighbouring axons and synapses, and as such many aspects of glial cell development and function are influenced by the activity of neural circuits. However, these AMPAR also render glia sensitive to elevations of the extracellular concentration of glutamate, which are associated with a broad range of pathological conditions. Excessive activation of AMPAR under these conditions may induce excitotoxic injury in glial cells, and trigger pathophysiological responses threatening other neural cells and amplifying ongoing disease processes. The aim of this review is to gather information on AMPAR function from across the broad diversity of glial cells, identify their contribution to pathophysiological processes, and highlight new areas of research whose progress may increase our understanding of nervous system dysfunction and disease.
Highlights
Glutamatergic signaling through alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptors (AMPAR) forms a major component of excitatory synaptic transmission in the central nervous system (CNS)
In this review we provide an overview of AMPAR expression in glial cells of the CNS and peripheral nervous system (PNS), describing functions for these receptors in physiological conditions, highlighting their involvement in glial responses to pathophysiological conditions, and hypothesising on additional roles that glial AMPAR may perform in the context of nervous system injury and disease
The following sections provide a review of each glial cell type, considering AMPAR expression, describing the known functions for these receptors in physiological and pathophysiological conditions, and highlighting emergent actions that stimulation of these AMPAR may evoke in the context of nervous system injury and disease
Summary
Glutamatergic signaling through alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptors (AMPAR) forms a major component of excitatory synaptic transmission in the central nervous system (CNS). Glutamate release in the CNS is not exclusive to synaptic terminals, and arises from unmyelinated axons [1] and non-neuronal glial cells [2] under both physiological and pathophysiological conditions. Glutamate is present at varying concentrations in a number of extra-synaptic locations where it influences non-neuronal AMPAR, those expressed by CNS glia cells, leading to influences on a range of critical functions. In this review we provide an overview of AMPAR expression in glial cells of the CNS and peripheral nervous system (PNS), describing functions for these receptors in physiological conditions, highlighting their involvement in glial responses to pathophysiological conditions, and hypothesising on additional roles that glial AMPAR may perform in the context of nervous system injury and disease. The review will indicate areas for future research, including cannabinoid AMPAR interactions, and AMPAR-stimulated transcriptional regulation, whose investigation promises to stimulate new knowledge on mechanisms regulating injury and disease processes, and identify new targets for CNS protection and repair
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