Absence of the bile acid enzyme CYP8B1 increases brain chenodeoxycholic acid and reduces neuronal excitotoxicity in mice

Abstract

Background: Bile acids (BAs), which act in the liver-brain axis, are liver-derived signaling molecules found in the brain. However, how they modulate neurological function remains largely unknown. Methods: To assess the role of BAs in the brain, we generated mice with absent 12-αhydroxylase (Cyp8b1), a BA synthesis enzyme, and determined if brain BA levels were altered in these mice, and if and how this may modulate neuronal function. Results: The absence of CYP8B1 increased brain levels of the primary BA chenodeoxycholic acid (CDCA), and decreased ischemic stroke infarct area. Furthermore, CDCA administration reduced ischemic stroke lesion area in wild-type mice. Excitotoxicity due to elevated extra-cellular glutamate contributes to neuronal death in ischemic stroke. Neurons from Cyp8b1-/- mice showed reduced susceptibility to glutamate-induced toxicity, and exogenous CDCA reduced glutamate-induced toxicity in neurons from wild-type mice. These data suggest that CDCA-mediated decreases in excitotoxic neuronal death contributes to the reduced stroke lesion area in Cyp8b1-/- mice. Aberrant N-methyl-D-aspartate receptor (NMDAR) over-activation contributes to excitotoxicity. CDCA decreased NMDAR-mediated excitatory post-synaptic currents (EPSCs) in wild-type brain slices, by reducing over-activation of the NMDAR subunit GluN2B. In line with this, synaptic NMDAR activity was also decreased in Cyp8b1-/- brain slices. Expression level and synaptic distribution of GluN2B were unaltered in Cyp8b1-/- mice, suggesting that CDCA may directly antagonize GluN2B-containing NMDARs. Conclusions: Our data suggests that CDCA acts in the liver-brain axis and decreases the aberrant over-activation of neuronal GluN2B-containing NMDARs, contributing to neuroprotection.