Oxidative-stress induced increase in circulating fatty acids does not contribute to phospholipase A2-dependent appetitive long-term memory failure in the pond snail Lymnaea stagnalis

Abstract

BackgroundReactive oxygen species (ROS) are essential for normal physiological functioning of the brain. However, uncompensated increase in ROS levels may results in oxidative stress. Phospholipase A2 (PLA2) is one of the key players activated by elevated ROS levels resulting in the hydrolysis of various products from the plasmamembrane such as peroxidized fatty acids. Free fatty acids (FFAs) and fatty acid metabolites are often implicated to the genesis of cognitive impairment. Previously we have shown that age-, and experimentally induced oxidative stress causes PLA2-dependent long-term memory (LTM) failure in an aversive operant conditioning model in Lymnaea stagnalis. In the present study, we investigate the effects of experimentally induced oxidative stress and the role of elevated levels of circulating FFAs on LTM function using a non-aversive appetitive classical conditioning paradigm.ResultsWe show that intracoelomic injection of exogenous PLA2 or pro-oxidant induced PLA2 activation negatively affects LTM performance in our learning paradigm. In addition, we show that experimental induction of oxidative stress causes significant temporal changes in circulating FFA levels. Importantly, the time of training coincides with the peak of this change in lipid metabolism. However, intracoelomic injection with exogenous arachidonic acid, one of the main FFAs released by PLA2, does not affect LTM function. Moreover, sequestrating circulating FFAs with the aid of bovine serum albumin does not rescue pro-oxidant induced appetitive LTM failure.ConclusionsOur data substantiates previous evidence linking lipid peroxidation and PLA2 activation to age- and oxidative stress-related cognitive impairment, neuronal dysfunction and disease. In addition however, our data indicate that lipid peroxidation induced increased levels of circulating (per)oxidized FFAs are not a factor in oxidative stress induced LTM impairment.

Phospholipase A2 – nexus of aging, oxidative stress, neuronal excitability, and functional decline of the aging nervous system? Insights from a snail model system of neuronal aging and age-associated memory impairment

“…As described above, aging Lymnaea display associative LTM impairment in two functionally and anatomically distinct (i.e., appetitive and respiratory) learning paradigms ( Hermann et al, 2007 , 2013 ; Watson et al, 2012a , 2013 , 2014 ; Beaulieu et al, 2014 ). In both instances, LTM failure was associated with reduced spontaneous action potential activity and enhanced spike frequency adaptation of the two key interneurons underlying both execution and plasticity of the respective behaviors (i.e., CGCs and RPeD1).…”

“…Both behavioral and electrophysiological facets of age-associated respiratory and appetitive LTM impairment could be reproduced in young animals through treatment with 2,2′- azobis-2-methyl-propanimidamide (AAPH), a water-soluble free radical generator commonly used to induce PUFA peroxidation, furthering the notion of plasmamembrane lipid peroxidation as a significant agent of neuronal and behavioral aging in Lymnaea ( Figure 8 ). Evidence of increased FFA mobilization from brains and other tissues was found in both old and AAPH-treated young animals ( Watson et al, 2013 ; Beaulieu et al, 2014 ). Moreover, treatment with the lipid-domain anti-oxidant α-tocopherol reversed decline in neuronal excitability in both experimental oxidative stressed and naturally aged neurons ( Watson et al, 2012a , b ).…”

“…Since then publications on various cell biological, endocrinological, neurophysiological, biophysical, behavioral, and reproductive aspects of aging in Lymnaea have appeared ( Frolkis et al, 1989 , 1991 ; Janse et al, 1989 , 1999 ; Wildering et al, 1991 ; Klaassen et al, 1998 ; Janse and van der Roest, 2001 ; Arundell et al, 2006 ; Patel et al, 2006 , 2010 ). Its use in research of the molecular and cellular foundations of AMI started in earnest with Hermann et al (2007) followed by a series of other publications from our laboratory linking AMI and neuronal excitability changes to oxidative stress, inflammation, lipid peroxidation and declining glutathione (GSH) availability, and identifying PLA 2 as a central player in these phenomena ( Watson et al, 2012a , b , 2013 , 2014 ; Hermann et al, 2013 ; Beaulieu et al, 2014 ).…”

Linking the why and how of aging; evidence for somatotropic control of long-term memory function in the pond snail Lymnaea stagnalis

“…Appetitive classical conditioning paradigm LTM performance was assessed 10-12 days after surgery using an established single-day, multi-trial appetitive classical conditioning protocol (Hermann et al, 2007(Hermann et al, , 2013Watson et al, 2012b;Beaulieu et al, 2014). Snails were sampled at random and marked for identification purposes with indelible marker.…”

Eicosanoids Derived From Arachidonic Acid and Their Family Prostaglandins and Cyclooxygenase in Psychiatric Disorders

“…Lipid peroxidation has been shown to contribute to pathophysiology of many psychiatric disease including neurodegenerative disorders [ 17 ] and autism spectrum disorder (ASD) [ 18 , 19 ]. In this regard, PLA2 activation induced by oxidative stress contributes to cognitive impairment, neuronal dysfunction and disease [ 20 ] and neurodegenerative diseases [ 21 ].…”