Abstract
BackgroundLipopolysaccharide (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.MethodsExtracellular 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.ResultsSystemic 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.ConclusionsGiven 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.
Highlights
Peripheral lipopolysaccharide (LPS) injection is widely known to induce sickness behaviour [1,2,3,4,5,6], mediated primarily via the inflammatory cytokines IL-1β [6], IL-6 [7] and TNF-α [6]
Two stimulations (50 ms apart) of layer IV/V with a concentric bipolar electrode typically showed 20% to 40% suppression of the second field postsynaptic potentials (fPSP) that could be abolished by washing the GABAA antagonist bicuculline (2 μM) over the slice in the perfusate (Figure 1B,C,D)
Our results show that systemic LPS injection reduces CNS inhibitory networks (Figure 4) and alters the temporal dynamics of neuromodulator activity (Figure 5) by increasing monoamine oxidase-A (MAO-A) (Figure 7) and ACh-E (Figure 8) activity
Summary
Peripheral lipopolysaccharide (LPS) injection is widely known to induce sickness behaviour [1,2,3,4,5,6], mediated primarily via the inflammatory cytokines IL-1β [6], IL-6 [7] and TNF-α [6]. Transduction of this peripheral response into the CNS is accomplished via indirect stimulation of vagal sensory nerve activity [8,9] as well as more direct effects transduced through endothelial prostaglandin synthesis [2], activation of macrophage-like cells in the circumventricular organs, and direct transduction across the blood brain barrier [10] to activate local microglial cells [11]. 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
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