Dietary threonine enhances sleep drive via a circadian clock-independent GABAergic pathway

Abstract

Amino acids are often used as sleep-inducing supplements; however, the neural basis underlying their sleep regulation remains unclear. Here we demonstrate sleep-promoting effects of dietary threonine (SPET) in Drosophila. Dietary threonine markedly increased the daily amount of sleep and shortened latency to sleep onset in a dose-dependent manner. SPET did not require the functionality of circadian clock genes or pacemaker neurons. By contrast, constitutively high levels of synaptic GABA or silencing of the GABA transmission, likely via the metabotropic GABA receptor, masked SPET. Dietary threonine activated a subset of GABAergic neurons, modulated GABA signaling in a homeostatic sleep locus, and ameliorated behavioral deficits in memory mutants. Moreover, genetic elevation of endogenous threonine levels in neurons was sufficient for enhancing sleep drive. Taken together, these data support the physiological relevance of SPET and define threonine as a sleep-promoting molecule that may intimately link neuronal metabolism of amino acids to sleep regulation.