Roles for the cyclooxygenases (especially COX 2) in learning and memory, as well as in synaptic plasticity.

The Morris water maze task has been used to de...
The Morris water maze task has been used to demonstrate the necessity of NMDA receptors in establishing spatial memories. (Photo credit: Wikipedia)

A pair of papers which focus on the role the inducible inflammatory regulating enzyme COX2 plays in learning and memory. These papers proceeded from earlier work of ours, showing that the bacterial endotoxin lipopolysaccharide (LPS) blocked synaptic plasticity but not synaptic transmission CA1-subiculum pathway in vivo. LPS induces the expression of COX2, amongst other things, and it seemed reasonable to then investigate what the inhibition of COX2 expression might lead to.

We were able to use at first non-selective and then selective inhibitors of the COX 2 enzyme to show that COX 2 inhibition inhibits synaptic plasticity and learning and memory, and that these deficits could be reversed by either exercise-induced increases in BDNF (Shaw et al: download the paper) or local application of prostaglandins (Cowley et al: download the paper).

Eur J Neurosci. 2003 Jun;17(11):2438-46.

Deficits in spatial learning and synaptic plasticity induced by the rapid and competitive broad-spectrum cyclooxygenase inhibitor ibuprofen are reversed by increasing endogenous brain-derived neurotrophic factor.

Shaw KNCommins SO’Mara SM.

Cyclooxygenase (COX), which is present in two isoforms (COX1 and 2), synthesizes prostaglandins from arachidonic acid; it plays a crucial role in inflammation in both central and peripheral tissues. Here, we describe its role in synaptic plasticity and spatial learning in vivo via an effect on brain-derived neurotrophic factor (BDNF) and prostaglandin E2 (PGE2; both measured by Elisa). We found that broad-spectrum COX inhibition (BSCI) inhibits the induction of long-term potentiation (LTP; the major contemporary model of synaptic plasticity), and causes substantial and sustained deficits in spatial learning in the watermaze. Increases in BDNF and PGE2 following spatial learning and LTP were also blocked. Importantly, 4 days of prior exercise in a running wheel increased endogenous BDNF levels sufficiently to reverse the BSCI of LTP and spatial learning, and restored a parallel increase in LTP and learning-related BDNF and PGE2. In control experiments, we found that BSCI had no effect on baseline synaptic transmission or on the nonhippocampal visible-platform task; there was no evidence of gastric ulceration from BSCI. COX2 is inhibited by glucorticoids; there was no difference in blood corticosterone levels as measured by radioimmunoassay in any condition. Thus, COX plays a previously undescribed, permissive role in synaptic plasticity and spatial learning via a BDNF-associated mechanism.

PMID: 12814375

Eur J Neurosci. 2008 Jun;27(11):2999-3008. doi: 10.1111/j.1460-9568.2008.06251.x. Epub 2008 Jun 6.

COX-2, but not COX-1, activity is necessary for the induction of perforant path long-term potentiation and spatial learning in vivo.

Cowley TRFahey BO’Mara SM.

The objectives of this research were to investigate the role played by the enzyme cyclooxygenase (COX) in learning and memory, synaptic plasticity and synaptic transmission in the rat brain in vivo. Male Wistar rats were treated with isoform-selective inhibitors for COX-1 and COX-2, either chronically and tested in the watermaze or acutely before electrophysiological recordings were made. We found a significant impairment in acquisition of the watermaze with inhibition of COX-2. Furthermore, we found COX-2 but not COX-1 inhibition significantly blocked long-term potentiation (LTP) induction but had no effect on already established LTP. Moreover, exogenous replacement of the main metabolite of COX-2 activity, PGE(2), was sufficient to restore LTP induction and for normal downstream signalling to ensue, namely extracellular signalling-regulated kinase (ERK)-phosphorylation and c-FOS expression. We conclude that endogenous basal levels of PGE(2) resulting from COX-2 but not COX-1 activity are necessary for synaptic plasticity and memory acquisition.

PMID:18540883

Author: Shane O'Mara

Neuroscientist

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