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Evidence for inflammation-mediated memory dysfunction in gastropods: putative PLA2 and COX inhibitors abolish long-term memory failure induced by systemic immune challenges.

Hermann PM, Park D, Beaulieu E, Wildering WC - BMC Neurosci (2013)

Bottom Line: This study investigated the effect of biologically realistic challenges of L. stagnalis host defense response system on LTM function and potential involvement of PLA2, COX and LOX therein.This effect dissipated within 24 hrs after treatment.Our findings underwrite the rapidly expanding view of neuroinflammatory processes as a fundamental, evolutionary conserved cause of cognitive and other nervous system disorders.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, AB T2N 1N4, Canada.

ABSTRACT

Background: Previous studies associate lipid peroxidation with long-term memory (LTM) failure in a gastropod model (Lymnaea stagnalis) of associative learning and memory. This process involves activation of Phospholipase A2 (PLA2), an enzyme mediating the release of fatty acids such as arachidonic acid that form the precursor for a variety of pro-inflammatory lipid metabolites. This study investigated the effect of biologically realistic challenges of L. stagnalis host defense response system on LTM function and potential involvement of PLA2, COX and LOX therein.

Results: Systemic immune challenges by means of β-glucan laminarin injections induced elevated H2O2 release from L. stagnalis circulatory immune cells within 3 hrs of treatment. This effect dissipated within 24 hrs after treatment. Laminarin exposure has no direct effect on neuronal activity. Laminarin injections disrupted LTM formation if training followed within 1 hr after injection but had no behavioural impact if training started 24 hrs after treatment. Intermediate term memory was not affected by laminarin injection. Chemosensory and motor functions underpinning the feeding response involved in this learning model were not affected by laminarin injection. Laminarin's suppression of LTM induction was reversed by treatment with aristolochic acid, a PLA2 inhibitor, or indomethacin, a putative COX inhibitor, but not by treatment with nordihydro-guaiaretic acid, a putative LOX inhibitor.

Conclusions: A systemic immune challenge administered shortly before behavioural training impairs associative LTM function in our model that can be countered with putative inhibitors of PLA2 and COX, but not LOX. As such, this study establishes a mechanistic link between the state of activity of this gastropod's innate immune system and higher order nervous system function. Our findings underwrite the rapidly expanding view of neuroinflammatory processes as a fundamental, evolutionary conserved cause of cognitive and other nervous system disorders.

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PLA2 inhibition restores LTM deficiency in laminarin treated animals. A. Protocol indicating timing of injection and start of pre- and post training tests with respect to the start of the first training session for both the conditioned (CS-UCS) and control (CS-DS) animals. B. LTM assessment in animals treated with either vehicle, laminarin, aristolochic acid (aristo acid) or a combined treatment of laminarin plus aristolochic acid (lamin + aristo acid). The laminarin treated conditioned group, showed a significant reduction in their Δrasp values in the post-training test compared to all other conditioned groups. Animals treated with aristolochic acid only or laminarin + aristolochic acid were not different in their conditioned response than the vehicle treated animals. This suggests that co-treatment of laminarin with a PLA2 inhibitor reverses the laminarin induced adverse effect on LTM performance. * = p < 0.05, *** p < 0.001, ns = not significant.
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Figure 6: PLA2 inhibition restores LTM deficiency in laminarin treated animals. A. Protocol indicating timing of injection and start of pre- and post training tests with respect to the start of the first training session for both the conditioned (CS-UCS) and control (CS-DS) animals. B. LTM assessment in animals treated with either vehicle, laminarin, aristolochic acid (aristo acid) or a combined treatment of laminarin plus aristolochic acid (lamin + aristo acid). The laminarin treated conditioned group, showed a significant reduction in their Δrasp values in the post-training test compared to all other conditioned groups. Animals treated with aristolochic acid only or laminarin + aristolochic acid were not different in their conditioned response than the vehicle treated animals. This suggests that co-treatment of laminarin with a PLA2 inhibitor reverses the laminarin induced adverse effect on LTM performance. * = p < 0.05, *** p < 0.001, ns = not significant.

Mentions: Considering PLA2’s pivotal role in the orchestration of key facets of the inflammatory response in many model systems, we next probed PLA2’s involvement in the laminarin induced LTM deficits presented above. To test this idea, four groups of animals that received, respectively, intracoelomic injections of either laminarin, aristolochic acid, laminarin + aristolochic acid or vehicle-only were behaviourally assessed as described before (Figure 6A). The results of these experiments are summarized in Figure 6B.


Evidence for inflammation-mediated memory dysfunction in gastropods: putative PLA2 and COX inhibitors abolish long-term memory failure induced by systemic immune challenges.

Hermann PM, Park D, Beaulieu E, Wildering WC - BMC Neurosci (2013)

PLA2 inhibition restores LTM deficiency in laminarin treated animals. A. Protocol indicating timing of injection and start of pre- and post training tests with respect to the start of the first training session for both the conditioned (CS-UCS) and control (CS-DS) animals. B. LTM assessment in animals treated with either vehicle, laminarin, aristolochic acid (aristo acid) or a combined treatment of laminarin plus aristolochic acid (lamin + aristo acid). The laminarin treated conditioned group, showed a significant reduction in their Δrasp values in the post-training test compared to all other conditioned groups. Animals treated with aristolochic acid only or laminarin + aristolochic acid were not different in their conditioned response than the vehicle treated animals. This suggests that co-treatment of laminarin with a PLA2 inhibitor reverses the laminarin induced adverse effect on LTM performance. * = p < 0.05, *** p < 0.001, ns = not significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750374&req=5

Figure 6: PLA2 inhibition restores LTM deficiency in laminarin treated animals. A. Protocol indicating timing of injection and start of pre- and post training tests with respect to the start of the first training session for both the conditioned (CS-UCS) and control (CS-DS) animals. B. LTM assessment in animals treated with either vehicle, laminarin, aristolochic acid (aristo acid) or a combined treatment of laminarin plus aristolochic acid (lamin + aristo acid). The laminarin treated conditioned group, showed a significant reduction in their Δrasp values in the post-training test compared to all other conditioned groups. Animals treated with aristolochic acid only or laminarin + aristolochic acid were not different in their conditioned response than the vehicle treated animals. This suggests that co-treatment of laminarin with a PLA2 inhibitor reverses the laminarin induced adverse effect on LTM performance. * = p < 0.05, *** p < 0.001, ns = not significant.
Mentions: Considering PLA2’s pivotal role in the orchestration of key facets of the inflammatory response in many model systems, we next probed PLA2’s involvement in the laminarin induced LTM deficits presented above. To test this idea, four groups of animals that received, respectively, intracoelomic injections of either laminarin, aristolochic acid, laminarin + aristolochic acid or vehicle-only were behaviourally assessed as described before (Figure 6A). The results of these experiments are summarized in Figure 6B.

Bottom Line: This study investigated the effect of biologically realistic challenges of L. stagnalis host defense response system on LTM function and potential involvement of PLA2, COX and LOX therein.This effect dissipated within 24 hrs after treatment.Our findings underwrite the rapidly expanding view of neuroinflammatory processes as a fundamental, evolutionary conserved cause of cognitive and other nervous system disorders.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, AB T2N 1N4, Canada.

ABSTRACT

Background: Previous studies associate lipid peroxidation with long-term memory (LTM) failure in a gastropod model (Lymnaea stagnalis) of associative learning and memory. This process involves activation of Phospholipase A2 (PLA2), an enzyme mediating the release of fatty acids such as arachidonic acid that form the precursor for a variety of pro-inflammatory lipid metabolites. This study investigated the effect of biologically realistic challenges of L. stagnalis host defense response system on LTM function and potential involvement of PLA2, COX and LOX therein.

Results: Systemic immune challenges by means of β-glucan laminarin injections induced elevated H2O2 release from L. stagnalis circulatory immune cells within 3 hrs of treatment. This effect dissipated within 24 hrs after treatment. Laminarin exposure has no direct effect on neuronal activity. Laminarin injections disrupted LTM formation if training followed within 1 hr after injection but had no behavioural impact if training started 24 hrs after treatment. Intermediate term memory was not affected by laminarin injection. Chemosensory and motor functions underpinning the feeding response involved in this learning model were not affected by laminarin injection. Laminarin's suppression of LTM induction was reversed by treatment with aristolochic acid, a PLA2 inhibitor, or indomethacin, a putative COX inhibitor, but not by treatment with nordihydro-guaiaretic acid, a putative LOX inhibitor.

Conclusions: A systemic immune challenge administered shortly before behavioural training impairs associative LTM function in our model that can be countered with putative inhibitors of PLA2 and COX, but not LOX. As such, this study establishes a mechanistic link between the state of activity of this gastropod's innate immune system and higher order nervous system function. Our findings underwrite the rapidly expanding view of neuroinflammatory processes as a fundamental, evolutionary conserved cause of cognitive and other nervous system disorders.

Show MeSH
Related in: MedlinePlus