Selective reduction of excitatory hippocampal sharp waves by docosahexaenoic acid and its methyl ester analog ex-vivo

Excitatory sharp waves (SPWs) originating from the hippocampus are considered to model the interictal "spikes" that occur in people with temporal lobe epilepsy. Docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid that has been reported to reduce neuronal excitability in vitro. The effect of DHA on hippocampal SPWs, however, is not known. Our goal was to determine whether DHA suppresses SPWs in thick mouse hippocampal slices, and to compare its effects with those of oleic acid (OA, control) and the standard anticonvulsant carbamazepine (CBZ). Also tested, were DHA's structural PUFA analogs n-3 docosapentaenoic acid (n-3 DPA), n-6 docosapentaenoic acid (n-6 DPA) and DHA-methyl ester (DHA-Me). The possible involvement of GABAergic activity was also examined using GABA receptor blockers. Extracellular recordings from CA1 and CA3 regions in hippocampal slices revealed that DHA reduced the incidence of SPWs. CBZ also reduced the incidence of SPWs and was 5 time more potent than DHA. DHA's effects on SPWs was abolished in the presence of GABA-receptor blockers, suggesting involvement of the GABA system in reducing excitatory SPWs. (14)C-DHA application to the slices confirmed the incorporation of DHA into membrane phospholipids. N-3 DPA and n-6 DPA, however, which also incorporate into phospholipids, had no effect on SPWs, while DHA-Me, a DHA analog that does not incorporate into membrane phospholipids, was effective at reducing them. We conclude that DHA, but not its n-3 and n-6 analogs, reduces network excitability of the recurrent CA3 circuitry in the mouse hippocampus. This reduction may be mediated by DHA in its unesterified form, and is likely related to a modulatory effect of DHA on GABAergic activity.