Systemic lipopolysaccharide-mediated alteration of cortical neuromodulation involves increases in monoamine oxidase-A and acetylcholinesterase activity

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. © ming et al.