title: Systemic lipopolysaccharide-mediated alteration of cortical neuromodulation involves increases in monoamine oxidase-A and acetylcholinesterase activity.
abstract: BACKGROUND
  Lipopolysaccharide (LPS)-mediated sickness behaviour is known to be a result of increased inflammatory cytokines in the brain. Inflammatory cytokines have been shown to mediate increases in brain excitation by loss of GABAA-mediated inhibition through receptor internalization or inactivation. Inflammatory pathways, reactive oxygen species and stress are also known to increase monoamine oxidase-A (MAO-A) and acetylcholinesterase (ACh-E) activity. Given that neuromodulator actions on neural circuits largely depend on inhibitory pathways and are sensitive to alteration in corresponding catalytic enzyme activities, we assessed the impact of systemic LPS on neuromodulator-mediated shaping of a simple cortical network.
  
  
  METHODS
  Extracellular field recordings of evoked postsynaptic potentials in adult mouse somatosensory cortical slices were used to evaluate effects of a single systemic LPS challenge on neuromodulator function 1 week later. Neuromodulators were administered transiently as a bolus (100 μl) to the bath perfusate immediately upstream of the recording site to mimic phasic release of neuromodulators and enable assessment of response temporal dynamics.
  
  
  RESULTS
  Systemic LPS administration resulted in loss of both spontaneous and evoked inhibition as well as alterations in the temporal dynamics of neuromodulator effects on a paired-pulse paradigm. The effects on neuromodulator temporal dynamics were sensitive to the Monoamine oxidase-A (MAO-A) antagonist clorgyline (for norepinephrine and serotonin) and the ACh-E inhibitor donepezil (for acetylcholine). This is consistent with significant increases in total MAO and ACh-E activity found in hemi-brain samples from the LPS-treated group, supporting the notion that systemic LPS administration may lead to longer-lasting changes in inhibitory network function and enzyme (MAO/ACh-E) activity responsible for reduced neuromodulator actions.
  
  
  CONCLUSIONS
  Given the significant role of neuromodulators in behavioural state and cognitive processes, it is possible that an inflammatory-mediated change in neuromodulator action plays a role in LPS-induced cognitive effects and could help define the link between infection and neuropsychiatric/degenerative conditions.
authors.affiliation: Department of Pharmacology, University of Saskatchewan, 107 Wiggins road, Saskatoon, SK, S7N 5E5, Canada. zhi-ming@live.com.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Ming
authors.affiliation: Department of Pharmacology, University of Saskatchewan, 107 Wiggins road, Saskatoon, SK, S7N 5E5, Canada. caw991@mail.usask.ca.
authors.forename: Caitlin A
authors.initials: CA
authors.lastname: Wotton
authors.affiliation: Department of Pharmacology, University of Saskatchewan, 107 Wiggins road, Saskatoon, SK, S7N 5E5, Canada. robert.t.appleton@gmail.com.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Appleton
authors.affiliation: Veterinary Biomedical Sciences, University of Saskatchewan, 52 Campus Drive, Saskatoon, SK, S7N 5E5, Canada. j.ching0501@gmail.com.
authors.forename: John C
authors.initials: JC
authors.lastname: Ching
authors.affiliation: Veterinary Biomedical Sciences, University of Saskatchewan, 52 Campus Drive, Saskatoon, SK, S7N 5E5, Canada. matthew.loewen@usask.ca.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Loewen
authors.affiliation: Department of Pharmacology, University of Saskatchewan, 107 Wiggins road, Saskatoon, SK, S7N 5E5, Canada. greg.sawicki@usask.ca.|Department of Clinical Chemistry, Medical University of Wroclaw, Wybrzeże L. Pasteura 1, Wroclaw, 50-556, Poland. greg.sawicki@usask.ca.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Sawicki
authors.affiliation: Department of Pharmacology, University of Saskatchewan, 107 Wiggins road, Saskatoon, SK, S7N 5E5, Canada. lane.bekar@usask.ca.
authors.forename: Lane K
authors.initials: LK
authors.lastname: Bekar
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000110:Acetylcholinesterase / Q000378:metabolism*; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000494:pharmacology; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D019417:Hindlimb Suspension / Q000379:methods; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008995:Monoamine Oxidase / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D015306:Biogenic Monoamines; D058787:GABA-A Receptor Antagonists; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D008995:Monoamine Oxidase; D000110:Acetylcholinesterase; D000109:Acetylcholine; D001640:Bicuculline