Abstract
The membrane properties of isolated cultured microglia have been extensively studied but it is important to understand their properties in situ, where they protect the brain against infection, but also contribute to neurodegenerative diseases. Microglia and macrophages attack bacteria by generating reactive oxygen species, a process which involves NADPH oxidase pumping electrons out across the cell membrane. The resulting inward current evokes a depolarization, which would inhibit the activity of the NADPH oxidase if there were no charge-compensating current which moves positive charge out across the membrane. The mechanism of this charge compensation is controversial. In neutrophils and in cultured microglia a depolarization-activated H+ conductance has been proposed to provide charge compensation, and also to remove protons generated intracellularly by the NADPH oxidase. Alternatively, a depolarization-activated K+ conductance has been proposed to mediate charge compensation. Here we show that in microglia, either in the resting state or when activated by the bacterial coat component lipopolysaccharide, both in acute and in cultured hippocampal slices, no significant H+ current is detectable. This implies that the membrane properties of microglia in their normal cellular environment differ from those of cultured microglia (similarly, microglia generated a current in response to ATP but, unlike in culture, not to glutamate or GABA). Furthermore, the K+ current (Kv1.3) that is activated by lipopolysaccharide is inactivated by depolarization, making it unsuitable for mediating charge compensation on a long time scale at positive voltages. Instead, charge compensation may be mediated by a previously undescribed non-selective cation current.
Highlights
Microglia, the immune cells of the brain, constantly survey the brain microenvironment and respond to infection or injury
Journal Compilation a Federation of European Neuroscience Societies and Blackwell Publishing Ltd European Journal of Neuroscience, 28, 1146–1156 (‘acute’) slices are less likely than isolated cultured microglia to have dramatically changed their properties
In the hours after slicing, some microglia become activated by the slicing process [Stence et al (2001), cells can stay ramified for hours: see below and Boucsein et al (2000)], so we compared the properties of microglia in acute slices with those of microglia in organotypic cultured slices
Summary
The immune cells of the brain, constantly survey the brain microenvironment and respond to infection or injury. Brain microglia are activated to produce a ‘respiratory burst’, which generates reactive oxygen species (ROS), in particular superoxide and peroxynitrite, that cause the death of target cells (Demaurex & Petheo, 2005). In neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases, HIV and prion infection, and multiple sclerosis, ROS generated by microglia contribute to the death of neurons (reviewed by Block et al, 2007). ROS are produced as a result of the microglial enzyme NADPH oxidase expelling electrons across the cell membrane. In this process, H+ accumulates inside microglia and the cells are depolarized by the electron current. As excessive depolarization inhibits further expulsion of electrons (DeCoursey et al, 2003), a charge-compensating mechanism is required to limit the depolarization of the microglial cells and to maintain the activity of the NADPH oxidase
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