Abstract
Astrocytes have long been perceived only as structural and supporting cells within the central nervous system (CNS). However, the discovery that these glial cells may potentially express receptors capable of responding to endogenous neurotransmitters has resulted in the need to reassess astrocytic physiology. The aim of the current study was to characterise the expression of NMDA receptors (NMDARs) in primary human astrocytes, and investigate their response to physiological and excitotoxic concentrations of the known endogenous NMDAR agonists, glutamate and quinolinic acid (QUIN). Primary cultures of human astrocytes were used to examine expression of these receptors at the mRNA level using RT-PCR and qPCR, and at the protein level using immunocytochemistry. The functionality role of the receptors was assessed using intracellular calcium influx experiments and measuring extracellular lactate dehydrogenase (LDH) activity in primary cultures of human astrocytes treated with glutamate and QUIN. We found that all seven currently known NMDAR subunits (NR1, NR2A, NR2B, NR2C, NR2D, NR3A and NR3B) are expressed in astrocytes, but at different levels. Calcium influx studies revealed that both glutamate and QUIN could activate astrocytic NMDARs, which stimulates Ca2+ influx into the cell and can result in dysfunction and death of astrocytes. Our data also show that the NMDAR ion channel blockers, MK801, and memantine can attenuate glutamate and QUIN mediated cell excitotoxicity. This suggests that the mechanism of glutamate and QUIN gliotoxicity is at least partially mediated by excessive stimulation of NMDARs. The present study is the first to provide definitive evidence for the existence of functional NMDAR expression in human primary astrocytes. This discovery has significant implications for redefining the cellular interaction between glia and neurons in both physiological processes and pathological conditions.
Highlights
N-methyl D-aspartate (NMDA) receptors (NMDARs) are ligand-gated ion channels which form one group of ionotropic glutamate receptors in the central nervous system (CNS)
Astrocyte ionotropic glutamate receptors and in particular NMDA receptors (NMDARs) may play an important role in facilitating glial signalling in the CNS
We have shown that adult and foetal human primary astrocytes express all known NMDAR subunits including NR1
Summary
N-methyl D-aspartate (NMDA) receptors (NMDARs) are ligand-gated ion channels which form one group of ionotropic glutamate receptors in the CNS. These receptors are known to be expressed in neurons and are activated by neurotransmitters including glutamate and NMDA [1] as well as endogenous excitotoxins such as quinolinic acid [2]. NMDARs exist as heterotetrameric complexes at the surface membrane. NMDARs play an important role in facilitating learning and memory [3]. Recent studies have revealed that these membrane proteins may exist in other cell types [4,5,6,7]
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