Dysfunctional epileptic neuronal circuits and dysmorphic dendritic spines are mitigated by platelet-activating factor receptor antagonism

Sci Rep. 2016 Jul 22;6:30298. doi: 10.1038/srep30298.

Abstract

Temporal lobe epilepsy or limbic epilepsy lacks effective therapies due to a void in understanding the cellular and molecular mechanisms that set in motion aberrant neuronal network formations during the course of limbic epileptogenesis (LE). Here we show in in vivo rodent models of LE that the phospholipid mediator platelet-activating factor (PAF) increases in LE and that PAF receptor (PAF-r) ablation mitigates its progression. Synthetic PAF-r antagonists, when administered intraperitoneally in LE, re-establish hippocampal dendritic spine density and prevent formation of dysmorphic dendritic spines. Concomitantly, hippocampal interictal spikes, aberrant oscillations, and neuronal hyper-excitability, evaluated 15-16 weeks after LE using multi-array silicon probe electrodes implanted in the dorsal hippocampus, are reduced in PAF-r antagonist-treated mice. We suggest that over-activation of PAF-r signaling induces aberrant neuronal plasticity in LE and leads to chronic dysfunctional neuronal circuitry that mediates epilepsy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood Platelets / metabolism
  • Dendritic Spines / metabolism
  • Dendritic Spines / pathology
  • Disease Models, Animal
  • Epilepsy, Temporal Lobe / drug therapy*
  • Epilepsy, Temporal Lobe / genetics
  • Epilepsy, Temporal Lobe / metabolism*
  • Epilepsy, Temporal Lobe / pathology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Limbic Lobe / metabolism
  • Limbic Lobe / pathology
  • Mice
  • Neuronal Plasticity / drug effects
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Platelet Activating Factor / genetics
  • Platelet Activating Factor / metabolism*
  • Platelet Membrane Glycoproteins / antagonists & inhibitors
  • Platelet Membrane Glycoproteins / genetics
  • Platelet Membrane Glycoproteins / metabolism*
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*

Substances

  • Platelet Activating Factor
  • Platelet Membrane Glycoproteins
  • Receptors, G-Protein-Coupled
  • platelet activating factor receptor