Maintenance of Synaptic Stability Requires Calcium-Independent Phospholipase A₂Activity

Abstract

Phospholipases A2 (PLA2s) represent one of the largest groups of lipid-modifying enzymes. Over the years, significant advances have been made in understanding their potential physiological and pathological functions. Depending on their calcium requirement for activation, PLA2s are classified into calcium dependent and independent. This paper mainly focuses on brain calcium-independent PLA2 (iPLA2) and on the mechanisms by which they influence neuronal function and regulate synaptic plasticity. Particular attention will be given to the iPLA2 γ isoform and its role in the regulation of synaptic glutamate receptors. In particular, the paper discusses the possibility that brain iPLA2 γ deficiencies could destabilise normal synaptic operation and might contribute to the aetiology of some brain disorders. In this line, the paper presents new data indicating that iPLA2 γ deficiencies accentuate AMPA receptor destabilization and tau phosphorylation, which suggests that this iPLA2 isoform should be considered as a potential target for the treatment of Tau-related disorders.

Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better?

“…Calciumin-dependent PLA2 (iPLA2) was increased in the combination group vs. all other injury groups, regardless of treatment. This crucial molecule involved in metabolism of membrane phospholipids has been implicated in cognitive function and synaptic stability (Schaeffer et al, 2009; Allyson et al, 2012). Along with iPLA2, the DHA-regulated structural synaptic membrane molecule, syntaxin-3, as well as the neural plasticity markers brain derived neurotrophic factor (BDNF) and p-Trk B, were increased with the combination treatment regimen beyond that observed with the monotherapies (Wu et al, 2013).…”

Lipid biology of the podocyte—new perspectives offer new opportunities

“…80 However, whether cellular injury is the result of antibody deposition on the podocyte cell membrane and subsequent complement activation, or altered PLA 2 R signalling is unclear. Calcium-dependent and calcium-independent activation of PLA 2 R modulates synaptic plasticity and the function of glutamate receptors in neurons, 81 probably through the modulation of glycerophospholipids by PLA 2 . This observation combined with evidence that podocytes express functional glutamate receptors 82 may open new avenues of investigation into the biology of PLA 2 R and how autoantibodies against PLA 2 R might affect podocyte injury through lipid-dependent damage.…”

Slow Excitotoxicity in Alzheimer's Disease

“…Neuroprotective actions of DHA may result from downregulation of AMPA receptors in hippocampal membranes, and through the generation of resolvins and protectins, which have neuroprotective properties [190][191][192]. A recent study shows that iPLA 2 ␥ deficiencies accentuate AMPA receptor destabilization and tau phosphorylation, which suggests that this isoform may be a therapeutic target for tau-related disorders, including AD [193]. Together, the results indicate activation or upregulation of cPLA 2 and sPLA 2, and increase in arachidonic acid and phospholipid metabolites that aggravate neuronal injury; but downregulation of iPLA 2, and decrease in DHA and metabolites that reduce neuronal injury, in brain tissue of AD.…”