title: Vagal nerve stimulation blocks interleukin 6-dependent synaptic hyperexcitability induced by lipopolysaccharide-induced acute stress in the rodent prefrontal cortex.
abstract: The ratio between synaptic inhibition and excitation (sI/E) is a critical factor in the pathophysiology of neuropsychiatric disease. We recently described a stress-induced interleukin-6 dependent mechanism leading to a decrease in sI/E in the rodent temporal cortex. The aim of the present study was to determine whether a similar mechanism takes place in the prefrontal cortex, and to elaborate strategies to prevent or attenuate it. We used aseptic inflammation (single acute injections of lipopolysaccharide, LPS, 10mg/kg) as stress model, and patch-clamp recording on a prefrontal cortical slice preparation from wild-type rat and mice, as well as from transgenic mice in which the inhibitor of IL-6 trans-signaling sgp130Fc was produced in a brain-specific fashion (sgp130Fc mice). The anti-inflammatory reflex was activated either by vagal nerve stimulation or peripheral administration of the nicotinic α7 receptor agonist PHA543613. We found that the IL-6-dependent reduction in prefrontal cortex synaptic inhibition was blocked in sgp130Fc mice, or - in wild-type animals - upon application sgp130Fc. Similar results were obtained by activating the "anti-inflammatory reflex" - a neural circuit regulating peripheral immune response - by stimulation of the vagal nerve or through peripheral administration of the α7 nicotinic receptor agonist PHA543613. Our results indicate that the prefrontal cortex is an important potential target of IL-6 mediated trans-signaling, and suggest a potential new avenue in the treatment of a large class of hyperexcitable neuropsychiatric conditions, including epilepsy, schizophrenic psychoses, anxiety disorders, autism spectrum disorders, and depression.
authors.affiliation: University of Texas at Dallas, School of Behavioral and Brain Sciences, Richardson, TX, United States; University of Texas Southwestern, Department of Psychiatry, Dallas, TX, United States. Electronic address: franciscooscos86@hotmail.com.
authors.forename: Francisco
authors.initials: F
authors.lastname: Garcia-Oscos
authors.affiliation: University of Texas at Dallas, School of Behavioral and Brain Sciences, Richardson, TX, United States.
authors.forename: David
authors.initials: D
authors.lastname: Peña
authors.affiliation: University of Texas at Dallas, School of Behavioral and Brain Sciences, Richardson, TX, United States.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Housini
authors.affiliation: University of Texas at Dallas, School of Behavioral and Brain Sciences, Richardson, TX, United States.
authors.forename: Derek
authors.initials: D
authors.lastname: Cheng
authors.affiliation: University of Texas at Arlington, Department of Chemistry and Biochemistry, Arlington, TX, United States.
authors.forename: Diego
authors.initials: D
authors.lastname: Lopez
authors.affiliation: University of Texas at Dallas, School of Behavioral and Brain Sciences, Richardson, TX, United States.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Borland
authors.affiliation: Universidad Autónoma de San Luis Potosí, Facultad de Ciencias, San Luis Potosí, Mexico.
authors.forename: Roberto
authors.initials: R
authors.lastname: Salgado-Delgado
authors.affiliation: Universidad Autónoma de Yucatán, Centro de Investigaciones Regionales Hideyo Noguchi, Mérida, Yucatán, Mexico.
authors.forename: Humberto
authors.initials: H
authors.lastname: Salgado
authors.affiliation: University of Texas at Dallas, School of Natural Sciences and Mathematics, Richardson, TX, United States; Southern Methodist University, Department of Neuroscience, Dallas, TX, United States.
authors.forename: Santosh
authors.initials: S
authors.lastname: D'Mello
authors.affiliation: University of Texas at Dallas, School of Behavioral and Brain Sciences, Richardson, TX, United States.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Kilgard
authors.affiliation: Christian Albrecht University, Department of Biochemistry, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: University of Texas at Dallas, School of Behavioral and Brain Sciences, Richardson, TX, United States; Universidad Autónoma de San Luis Potosí, Facultad de Ciencias, San Luis Potosí, Mexico. Electronic address: marco.atzori@uaslp.mx.
authors.forename: Marco
authors.initials: M
authors.lastname: Atzori
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D015850:Interleukin-6 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000378:metabolism / Q000502:physiology*; D055536:Vagus Nerve Stimulation
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides
keywords: Anti-inflammatory reflex; GABA; Interleukin 6; Lipopolysaccharide; Vagal nerve stimulation