PGE2-EP3 signaling pathway impairs hippocampal presynaptic long-term plasticity in a mouse model of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by early cognitive deficits linked to synaptic dysfunction and loss. Considerable evidence suggests that neuroinflammation contributes to AD. Prostaglandin E₂ (PGE₂), a key neuroinflammatory molecule, modulates hippocampal synaptic transmission and plasticity. We investigated the effect of PGE₂ on synaptic transmission and presynaptic plasticity at synapses between mossy fibers from the dentate gyrus and CA3 pyramidal cells (Mf-CA3 synapse). These synapses are involved in mnemonic processes and consequently may be of relevance for AD. We provide evidence that although PGE₂ had no effect both on either basal transmission or short-term plasticity, it strongly impaired presynaptic Mf-CA3 long-term potentiation (LTP) by acting on PGE₂ receptor 3 (EP3) receptors. During aging, hippocampal levels of PGE₂ markedly increased in the APP/PS1 mouse model of AD and impaired specifically presynaptic LTP via a PGE₂-EP3 signaling pathway. In summary, the building up of PGE₂ during the progression of AD leads to specific impairment of hippocampal presynaptic plasticity and highlights EP3 receptors as a potential target to alleviate cognitive deficits in AD.

Keywords: APP/PS1; Alzheimer's disease; Hippocampus; Inflammation; PGE(2); Synaptic plasticity.