Endothelin-1 modulates hippocampal and hypothalamic neuronal network activity in mouse primary dissociated cultures...

Endothelin-1 (ET-1) is known not only as a vasoconstrictor, but also as a neuromodulator. It can reset the circadian clock and we hypothesized that it modulates neuronal excitability and network activity in histaminergic neurons (HN). HN, located in the tuberomammillary nucleus (TMN) of the caudal hypothalamus (cHPT), fire spontaneously during waking and promote arousal. Previous studies have shown that ET-1 reduces firing frequency of hippocampal pyramidal neurons, whereas its effects on electrophysiological properties of HN remain unknown. We now studied the expression of ET-receptors (ET_A and ET_B) in the hippocampus (HPC) and caudal hypothalamus by single-cell RT-PCR and qPCR. The responses to ET-1 were studied in HN and dentate gyrus granule cells (DGgc) of brain slices using patch-clamp recordings and primary cultures of cHPT and HPC using Microelectrode Arrays (MEAs). ET-1 significantly decreased firing frequency in HPC and increased it in cHPT cultures with prevailing inhibition of individual MEA channels in HPC and excitation in cHPT. Neuronal synchrony and bursting were significantly increased in cHPT. Relative to HPC, cHPT displayed higher expression of ET_B. In brain slices, ET-1 induced a delayed bosentan-sensitive increase in HN and decrease in DGgc firing frequency. HN expressed ET_B (15 of 22 HN) and ET_A (4 of 15 ET_B positive HN), whereas only ET_B was expressed in 50% of DGgc. We conclude that ET-1 differentially modulates cHPT and HPC. By exciting HN and synchronizing neuronal network activity in cHPT, ET-1 may contribute to cellular and circuit-level mechanisms in the regulation of arousal and wakefulness.