Abstract
Brain ischemia causes oxygen and glucose deprivation (OGD) in neurons, triggering a cascade of events leading to synaptic accumulation of glutamate. Excessive activation of glutamate receptors causes excitotoxicity and delayed cell death in vulnerable neurons. Following global cerebral ischemia, hippocampal CA1 pyramidal neurons are more vulnerable to injury than their cortical counterparts, but the mechanisms that underlie this difference are unclear. Signaling via Rho-family small GTPases, their upstream guanine nucleotide exchange factors, and GTPase-activating proteins (GAPs) is differentially dysregulated in response to OGD/ischemia in hippocampal and cortical neurons. Increased Rac1 activity caused by OGD/ischemia contributes to neuronal death in hippocampal neurons via diverse effects on NADPH oxidase activity and dendritic spine morphology. The Rac1 guanine nucleotide exchange factor Tiam1 mediates an OGD-induced increase in Rac1 activity in hippocampal neurons; however, the identity of an antagonistic GAP remains elusive. Here we show that the Rac1 GAP breakpoint cluster region (BCR) associates with NMDA receptors (NMDARs) along with Tiam1 and that this protein complex is more abundant in hippocampal compared with cortical neurons. Although total BCR is similar in the two neuronal types, BCR is more active in hippocampal compared with cortical neurons. OGD causes an NMDAR- and Ca2+-permeable AMPAR-dependent deactivation of BCR in hippocampal but not cortical neurons. BCR knockdown occludes OGD-induced Rac1 activation in hippocampal neurons. Furthermore, disrupting the Tiam1–NMDAR interaction with a fragment of Tiam1 blocks OGD-induced Tiam1 activation but has no effect on the deactivation of BCR. This work identifies BCR as a critical player in Rac1 regulation during OGD in hippocampal neurons.
Highlights
Brain ischemia causes oxygen and glucose deprivation (OGD) in neurons, triggering a cascade of events leading to synaptic accumulation of glutamate
We show that the Rac1 GTPase-activating proteins (GAPs) breakpoint cluster region (BCR) associates with NMDA receptors (NMDARs) along with Tiam1 and that this protein complex is more abundant in hippocampal compared with cortical neurons
Dissociated cultures of hippocampal neurons are more vulnerable to oxygen/glucose deprivation (OGD)3 than equivalent cultures prepared from cerebral cortex, suggesting that distinct cell type–specific mechanisms are activated in response to insult [4]
Summary
BCR is deactivated following OGD in hippocampal but not cortical neurons It has been shown previously that Tiam and BCR form a GEF–GAP complex that precisely controls Rac activation and thereby modulates dendritic spine development in hippocampal neurons [8]. OGD caused a decrease in Tiam binding to BCR in hippocampal neurons compared with control conditions (Fig. 4). The levels of total BCR were similar in the two cell types; there was a higher proportion of active, phosphorylated BCR in hippocampal neurons compared with cortical neurons (Fig. 5). Because down-regulating Tiam in hippocampal neurons protects hippocampal neurons from OGD-induced cell death, our results further suggest that the PHCCEx domain or similar disrupting peptide might prove to be a useful tool to disrupt aberrant signaling caused by ischemia in specific brain regions and may be neuroprotective
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