Bile acids are steroidal amphipathic molecules derived from the catabolism of cholesterol. They are not only important for the absorption of dietary lipids but are also signalling molecules with diverse endocrine and paracrine functions. Normally produced in the liver, they recirculate in the enterohepatic circuit. During cholestasis (stagnation of bile due to impaired outflow through the bile duct), bile acids and bilirubin accumulate in the blood. Bile salts at concentrations around 1 mM or even lower can modify the blood-brain barrier and pass through it. Accumulation of hydrophobic bile acids in the brain causes apoptosis, necrosis and oxidative stress, leading to the development of cholestatic encephalopathy. We investigated in the present study the interaction of cholate and deoxycholate with GABA_A and AMPA receptors in mouse histaminergic neurons of the posterior hypothalamus, controlling wakefulness. Bile salts blocked half-maximal GABA responses (IC₅₀ 0.6 and 0.3 mM for cholate and deoxycholate, respectively). The degree of block increased with membrane depolarisation. At maximal GABA-evoked currents, plateau but not peak amplitudes were mainly affected by bile salts. Spontaneous GABAergic IPSCs recorded from cultured hypothalamic neurons showed a dose-dependent decrease in frequency and were shortened in their decay kinetics by cholate (0.2–4mM), indicating post- and pre-synaptic modulation of GABAergic transmission. AMPA receptor-mediated responses (kainate, 100mM) were not affected by bile salts up to a concentration of 10 mM.

We conclude that blockade of brain GABA_ARs and inhibitory GABAergic neurotransmission by bile salts may change the balance between excitation and inhibition in neuronal circuits, thus contributing to the progression of cholestatic encephalopathy.