Deletion of TASK1 and TASK3 channels disrupts intrinsic excitability but does not abolish glucose or pH responses of orexin/hypocretin neurons

Abstract

The firing of hypothalamic hypocretin/orexin neurons is vital for normal sleep-wake transitions, but its molecular determinants are not well understood. It was recently proposed that TASK (TWIK-related acid-sensitive potassium) channels [TASK1 (K 2P 3.1) and/or TASK3 (K 2P 9.1)] regulate neuronal firing and may contribute to the specialized responses of orexin neurons to glucose and pH. Here we tested these theories by performing patch-clamp recordings from orexin neurons directly identified by targeted green fluorescent protein labelling in brain slices from TASK1/3 double-knockout mice. The deletion of TASK1/3 channels significantly reduced the ability of orexin cells to generate high-frequency firing. Consistent with reduced excitability, individual action potentials from knockout cells had lower rates of rise, higher thresholds and more depolarized after-hyperpolarizations. However, orexin neurons from TASK1/3 knockout mice retained typical responses to glucose and pH, and the knockout animals showed normal foodanticipatory locomotor activity. Our results support a novel role for TASK genes in enhancing neuronal excitability and promoting high-frequency firing, but suggest that TASK1/3 subunits are not essential for orexin cell responses to glucose and pH.

Molecular Physiology of pH-Sensitive Background K2P Channels

“…Glucose and acid inhibit a background K ϩ current promoting depolarization and enhanced excitability. However, pH and glucose responses are preserved in task1 Ϫ/Ϫ task3 Ϫ/Ϫ orexin neurons, ruling out TASK channels as exclusive sensors in these cells (46,51).…”

Multiple hypothalamic circuits sense and regulate glucose levels

“…54 and 40]. In orexin/hypocretin and MCH neurons, an equivalent analysis has not been performed due to the lack of knowledge of molecular components of glucose sensing in these cells (19,20,38). However, the original study by Yamanaka et al (110) that described the intrinsic inhibitory responses of orexin/ hypocretin cells to glucose also observed a lack of fastinginduced stimulation of arousal in mice lacking orexins/hypocretins, suggesting that disinhibition of orexin/hypocretin cells by falling glucose may have a role in the initiation of foraging.…”

Molecular Background of Leak K+Currents: Two-Pore Domain Potassium Channels

“…knock out mice showed reduced background K ϩ conductance and impaired high-frequency firing (119). However, glucose hyperpolarized and inhibited spontaneous action potential generation of orexin neurons in the knockout mice as efficiently as in the wild-type animals, and the acid sensitivity of the background K ϩ current was also maintained (119,124).…”

“…However, glucose hyperpolarized and inhibited spontaneous action potential generation of orexin neurons in the knockout mice as efficiently as in the wild-type animals, and the acid sensitivity of the background K ϩ current was also maintained (119,124). As the glucose-activated protonsensitive leak K ϩ current was also inhibited by low concentrations of Ba 2ϩ (which does not inhibit TASK channels), unidentified (41) or weakly inwardly rectifying K ir channels (124) were suggested to be responsible for sensing glucose concentration.…”