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

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 E (PGE), a key neuroinflammatory molecule, modulates hippocampal synaptic transmission and plasticity. We investigated the effect of PGE 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 PGE 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 PGE receptor 3 (EP3) receptors. During aging, hippocampal levels of PGE markedly increased in the APP/PS1 mouse model of AD and impaired specifically presynaptic LTP via a PGE-EP3 signaling pathway. In summary, the building up of PGE 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.