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

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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 (K2P3.1) and/or TASK3 (K2P9.1)] 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 food‐anticipatory 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.