PGE 2-EP3 signaling pathway impairs hippocampal presynaptic long-term plasticity in a mouse model of Alzheimer's disease

Neurobiol Aging. 2017 Feb;50:13-24. doi: 10.1016/j.neurobiolaging.2016.10.012. Epub 2016 Oct 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism*
  • Aging / physiology*
  • Alzheimer Disease / etiology*
  • Alzheimer Disease / therapy
  • Animals
  • Dinoprostone / physiology*
  • Disease Models, Animal
  • Hippocampus / physiopathology*
  • Long-Term Potentiation
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Targeted Therapy
  • Neuronal Plasticity / genetics*
  • Neuronal Plasticity / physiology*
  • Receptors, Prostaglandin E, EP3 Subtype / physiology*
  • Signal Transduction / physiology*
  • Synapses / physiology*
  • Synaptic Transmission / genetics*
  • Synaptic Transmission / physiology

Substances

  • PTGER3 protein, human
  • Receptors, Prostaglandin E, EP3 Subtype
  • Dinoprostone