Novel neuroprotection mechanism identified
MedWire News: UK researchers have identified a novel mechanism by which certain neurons are resistant to ischemic damage, in findings that could potentially lead to new therapeutic targets.
The study, by Jack Mellor (University of Bristol) and team, found that activation of a calcium-permeable AMPA receptor (AMPAR) had a neuroprotective effect during ischemia.
Mellor's team sought to resolve the question of why neurons in adjacent regions of the brain show differential sensitivity to ischemic damage. Specifically, hippocampal CA1 pyramidal neurons are highly sensitive to ischemic damage, whereas neighboring CA3 pyramidal neurons are less susceptible.
Previous work has shown that switching of AMPAR subunits on CA1 neurons during oxygen/glucose deprivation (OGD) - an established model of ischemia - leads to an enhanced permeability of AMPARs to calcium ions, resulting in delayed cell death.
In this study, the team investigated the impact of OGD in CA3 neurons. Using ex vivo slices of rat hippocampus, they found that 15 minutes of OGD produced a substantial and persistent depression of AMPAR-mediated responses that was specific to CA3 pyramidal neurons.
Further work showed that this was a postsynaptic event, independent of the NMDA receptor and AMPAR activity, and did not occur in CA1 neurons.
Instead, depression of AMPAR-mediated signals was mediated by activation of metabotropic glutamate receptor 1 and adenosine A3 receptors and led to AMPAR endocytosis and subsequent degradation.
"Thus, we describe a novel mechanism for the removal of AMPARs in CA3 pyramidal neurons following OGD that has the potential to reduce excitotoxicity and promote neuroprotection," write Mellor et al in the Journal of Neuroscience.
Commenting on the study in an accompanying press release, Mellor remarked: "Historically, stroke has been very difficult to treat because of its unpredictability and the need to administer drugs within minutes of the onset of a stroke.
"These problems will not be overcome by our research but our findings do reveal a natural protection mechanism in some nerve cells, which may be useful in developing treatments to protect other nerve cell types."
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By Joanna Lyford