Cyclooxygenase-2 regulates prostaglandin E₂ signaling in hippocampal long-term synaptic plasticity

The functional significance of cyclooxygenases (COX-1 and -2), the key enzymes that convert arachidonic acid (AA) to prostaglandins (PGs) in brain, is unclear, although they have been implicated in cellular functions and in some neurologic disorders, including stroke, epilepsy, and Alzheimer's disease. Recent evidence that COX-2 is expressed in postsynaptic dendritic spines (which are specialized structures involved in synaptic signaling) and is regulated by synaptic activity implies participation of COX-2 in neuronal plasticity. However, direct evidence is lacking. Here we demonstrate that selective COX-2 inhibitors significantly reduced postsynaptic membrane excitability, back-propagating dendritic action potential-associated Ca²⁺ influx, and long-term potentiation (LTP) induction in hippocampal dentate granule neurons, while a COX-1 inhibitor is ineffective. All of these actions were effectively reversed by exogenous application of PGE₂ but not of PGD₂ or PGF_2α. Our results indicate that COX-2-generated PGE₂ regulates membrane excitability and long-term synaptic plasticity in hippocampal perforant path-dentate gyrus synapses.