Calcium‐independent phospholipase A₂ influences AMPA‐mediated toxicity of hippocampal slices by regulating the GluR1 subunit in synaptic membranes

Abstract

We have recently documented that phosphorylation of the GluR1 subunit of alpha-amino-3-hydroxy-5-methylisoxazole-propionate (AMPA) glutamate receptors is influenced by calcium-independent forms of phospholipase A(2) (iPLA(2)) activity in the brain. Given the importance of GluR1 subunit phosphorylation in the control of AMPA receptor delivery to synaptic membranes, we tested the influence of iPLA(2) activity on AMPA receptor distribution between neuronal compartments, using organotypic cultured hippocampal slices. In agreement with earlier reports, the iPLA(2) inhibitor bromoenol lactone (BEL) markedly enhanced the phosphorylation of the GluR1 subunit at both Ser831 and Ser845 residues. GluR1 subunit phosphorylation levels were selectively increased by (R)-BEL, an enantio-selective inhibitor of iPLA(2)gamma, but not by (S)-BEL, an iPLA(2)beta inhibitor. The iPLA(2)gamma inhibitor R-BEL also promoted the insertion of new GluR1 subunits into synaptic membranes and exacerbated AMPA-mediated cell death in the CA1 region of the hippocampus. The latter effect was selectively abolished by IEM 1460 and philanthotoxin-433, two antagonists specific for AMPA receptors lacking GluR2 subunits. These results provide evidence that iPLA(2)gamma-related regulation of AMPA receptor GluR1 subunit phosphorylation could represent an important mechanism modulating hippocampal cell death induced by AMPA receptor overstimulation.

Glutamatergic signaling and low prodynorphin expression are associated with intact memory and reduced anxiety in rat models of healthy aging

“…NMDA-mediated synaptic plasticity involves efficient AMPA receptor trafficking (Huganir and Nicoll, 2013). However, insertion of GluR1 homomeric receptors in synaptic membranes can lead to AMPA-mediated excitotoxicity (Menard et al, 2007) as GluR2 subunits are recognized to confer calcium impermeability to AMPA receptors (Sommer et al, 1991; Geiger et al, 1995). Strain-related differences in hippocampal learning tasks and regulation of AMPA receptors have been previously reported in mice (Upchurch and Wehner, 1988, 1989; Rossi-Arnaud and Ammassari-Teule, 1998; Menard et al, 2004) but, to our knowledge, not in rats yet.…”

Genetic Ablation of Calcium-independent Phospholipase A2γ Leads to Alterations in Hippocampal Cardiolipin Content and Molecular Species Distribution, Mitochondrial Degeneration, Autophagy, and Cognitive Dysfunction

“…This region was selected because of its vital importance in learning and memory and from prior work that had demonstrated both the abundance of iPLA 2 activity in the hippocampus as well as the impact of pharmacologic inhibition of iPLA 2 on hippocampal function (15,42,43). Furthermore, in the current study, morphologic alterations appeared to be maximally present in the hippocampus (see below).…”

Neuropathological Disorders and Calcium Independent Forms of Phospholipase A2 Activities in the Brain

“…Hence, the reduction of iPLA 2 γ activity, by promoting surface expression of the GluR1 subunit over the GluR2 subunit (which is reflected by a rise in the GluR1/GluR2 ratio in the membrane fraction), could exacerbate excitotoxic cell death through the formation of GluR2-lacking AMPA receptors that would allow adverse Ca2+ influx upon prolonged AMPA receptor activation. Consistent with this possibility, the greater cell death observed under iPLA 2 γ inhibition is prevented by GluR2-lacking AMPA receptor antagonists (Menard et al, 2007). How inhibition of iPLA 2 γ influences the expression of AMPA receptor subtypes in synaptic membranes remains an open question.…”

“…In addition, recent findings from our laboratory have revealed that constitutive iPLA 2 γ activity might represent an important neuroprotective system capable of limiting brain excitotoxic damage. We have shown that inhibition of iPLA 2 γ by the enantio-specific inhibitor (R)-BEL makes hippocampal slice cultures more vulnerable to AMPA-mediated excitotoxicity (Menard et al, 2007). Overactivation of N-methyl-D-aspartic acid (NMDA) or AMPA glutamatergic receptors, allowing the entry of high cation levels into cells, activates a number of enzymes, including ATPases, lipases, proteases and endonucleases that, in turn, deplete energy stores or damage cell membranes, cytoarchitecture or nucleus, respectively.…”

“…Excitotoxicity has been reported to contribute to a variety of neuropathological disorders, including ischemic stroke, epilepsy, amyotrophic lateral sclerosis and Alzheimer's disease (AD) (Kwak & Weiss, 2006;Villmann & Becker, 2007). Interestingly, the harmful effect of iPLA 2 γ inhibition on AMPA-mediated toxicity is associated with selective up-regulation of AMPA receptor GluR1 subunit (but not GluR2) phosphorylation with a subsequently increased level in synaptic membrane fractions (Menard et al, 2007;Menard et al, 2005;Villmann & Becker, 2007). In the hippocampus, AMPA receptors generally form heterodimers containing 2 copies of each of the GluR1 and GluR2 subunits.…”