Abstract
Olfactory dysfunction is a common clinical phenomenon observed in various liver diseases. Previous studies have shown a correlation between smell disorders and bilirubin levels in patients with hepatic diseases. Bilirubin is a well-known neurotoxin; however, its effect on neurons in the main olfactory bulb (MOB), the first relay in the olfactory system, has not been examined. We investigated the effect of bilirubin (>3 μM) on mitral cells (MCs), the principal output neurons of the MOB. Bilirubin increased the frequency of spontaneous firing and the frequency but not the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs). TTX completely blocked sEPSCs in almost all of the cells tested. Bilirubin activity was partially blocked by N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepro pionic acid (AMPA) receptor antagonists. Furthermore, we found that bilirubin increased the frequency of intrinsic firing independent of synaptic transmission in MCs. Our findings suggest that bilirubin enhances glutamatergic transmission and strengthens intrinsic firing independent of synaptic transmission, all of which cause hyperexcitability in MCs. Our findings provide the basis for further investigation into the mechanisms underlying olfactory dysfunction that are often observed in patients with severe liver disease.
Highlights
We investigated the effect of bilirubin on Mitral cells (MCs) excitability because excitatory output from these cells reflects the encoding of odor information[23] which may be impaired in patients with hepatic disease owing to high serum bilirubin levels
We found that bilirubin significantly affected MC excitability, providing direct evidence that high bilirubin levels interfere with MC output and contribute to the olfactory dysfunction associated with liver disease
The excitotoxic effects of bilirubin have been documented in various central nervous system (CNS) areas, including the ventral cochlear nuclei, subthalamic nucleus, and hippocampus[13]
Summary
We investigated the effect of bilirubin on MC excitability because excitatory output from these cells reflects the encoding of odor information[23] which may be impaired in patients with hepatic disease owing to high serum bilirubin levels. We used patch-clamp techniques to investigate whether bilirubin induced hyperexcitation in MCs and to examine the underlying mechanisms. We found that bilirubin significantly affected MC excitability, providing direct evidence that high bilirubin levels interfere with MC output and contribute to the olfactory dysfunction associated with liver disease
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