Depressed by Dual Insults

Sci. Signal.  08 Apr 2014:
Vol. 7, Issue 320, pp. ec92
DOI: 10.1126/scisignal.2005341

Microglia are immune cells that reside in the brain and contribute to the removal of damaged tissue, which they partially recognize through the pattern recognition receptor complex complement receptor 3 (CR3). Bacterial products, such as lipopolysaccharide (LPS), constitute one set of ligands for CR3. Using electrophysiological analysis of brain slices from rats or from wild-type or CR3-knockout mice, Zhang et al. found that LPS when combined with hypoxia, but neither stimulus alone, caused CR3-dependent long-term depression (LTD) of the CA1 region in hippocampal slice preparations. This LTD required activation of the microglial NADPH oxidase, which is activated by LPS and produces reactive oxygen species (ROS), and was blocked by coapplication of its inhibitor apocynin or an NADPH oxidase-blocking peptide or by preincubation with a ROS scavenger. Hypoxic conditions enhance NADPH oxidase activity through alterations in metabolism that result in an increase in the lactate-to-pyruvate ratio, which increases the NADPH-to-NADP+ ratio. Coapplication of lactic acid with LPS triggered LTD in the absence of hypoxia, suggesting that this altered metabolism was the mechanism by which hypoxia contributed to the induction of LTD. ROS were produced in response to the combination of hypoxia and LPS treatment but not when either were applied separately. Protein phosphatase 2A (PP2A) is activated by ROS. Combined LPS and hypoxia stimulated PP2A activity, and inhibition of phosphatase activity with okadaic acid prevented the LPS- and hypoxia-induced LTD. LTD can be triggered in the synapses under investigation by endocytosis of AMPA receptors with the GluA2 subunit, and the neuroinflammatory-mediated LTD was inhibited by a peptide that interfered with GluA2-mediated AMPA receptor endocytosis. Thus, this represents a neuroinflammatory form of LTD that may contribute to the memory and synaptic defects associated with neuroinflammatory disorders, such as Alzheimer’s disease, as discussed by Collingridge and Peineau.

J. Zhang, A. Malik. H. B. Choi, R. W. Y. Ko, L. Dissing-Olesen, B. A. MacVicar, Microglial CR3 activation triggers long-term synaptic depression in the hippocampus via NADPH oxidase. Neuron 82, 1–13 (2014). [PubMed]

G. L. Collingridge, S. Peineau, Strippers reveal their depressing secrets: Removing AMPA receptors. Neuron 82, 3–6 (2014). [Abstract]

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