title: Dysfunctional epileptic neuronal circuits and dysmorphic dendritic spines are mitigated by platelet-activating factor receptor antagonism.
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.
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, 2020 Gravier Street, New Orleans, Louisiana 70112, USA.
authors.forename: Alberto E
authors.initials: AE
authors.lastname: Musto
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, 2020 Gravier Street, New Orleans, Louisiana 70112, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Rosencrans
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, 2020 Gravier Street, New Orleans, Louisiana 70112, USA.
authors.forename: Chelsey P
authors.initials: CP
authors.lastname: Walker
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, 2020 Gravier Street, New Orleans, Louisiana 70112, USA.
authors.forename: Surjyadipta
authors.initials: S
authors.lastname: Bhattacharjee
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, 2020 Gravier Street, New Orleans, Louisiana 70112, USA.|Department of Pediatrics, Hematology-Oncology, Louisiana State University Health Sciences Center and Children's Hospital of New Orleans, New Orleans, Louisiana 70118, USA.
authors.forename: Chittalsinh M
authors.initials: CM
authors.lastname: Raulji
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, 2020 Gravier Street, New Orleans, Louisiana 70112, USA.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Belayev
authors.affiliation: Biostatistics, School of Public Health, Louisiana State University Health Sciences Center, 2020 Gravier Street, New Orleans, Louisiana 70112, USA.
authors.forename: Zhide
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, 2020 Gravier Street, New Orleans, Louisiana 70112, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Gordon
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, 2020 Gravier Street, New Orleans, Louisiana 70112, USA.
authors.forename: Nicolas G
authors.initials: NG
authors.lastname: Bazan
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D065726:Limbic Lobe / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010972:Platelet Activating Factor / Q000235:genetics / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor