D-Serine made by serine racemase in Drosophila intestine plays a physiological role in sleep

Abstract

Natural D-serine (D-Ser) has been detected in animals more than two decades ago, but little is known about the physiological functions of D-Ser. Here we reveal sleep regulation by endogenous D-Ser. Sleep was decreased in mutants defective in D-Ser synthesis or its receptor the N-methyl-D-aspartic receptor 1 (NMDAR1), but increased in mutants defective in D-Ser degradation. D-Ser but not L-Ser rescued the phenotype of mutants lacking serine racemase (SR), the key enzyme for D-Ser synthesis. Pharmacological and triple gene knockout experiments indicate that D-Ser functions upstream of NMDAR1. Expression of SR was detected in both the nervous system and the intestines. Strikingly, reintroduction of SR into specific intestinal epithelial cells rescued the sleep phenotype of sr mutants. Our results have established a novel physiological function for endogenous D-Ser and a surprising role for intestinal cells.

High-Salt Diet Causes Sleep Fragmentation in Young Drosophila Through Circadian Rhythm and Dopaminergic Systems

“…Dietary quality and the intake of specific nutrients can affect hormonal signaling pathways to alter sleep duration and quality (Frank et al, 2017). For example, tryptophan is an amino acid precursor to the sleep-regulating hormone serotonin, and natural D-serine is an effective co-agonist of the N -methyl- D -aspartate subtype of glutamate receptor, which is involved in sleep regulation (Dai et al, 2019). There is also evidence linking HSD with increased levels of the hormone cortisol, and these excess levels may affect sleep (Baudrand et al, 2014).…”

Drosophila Glia: Models for Human Neurodevelopmental and Neurodegenerative Disorders

“…D-serine and its neuronal receptor have been implicated in sleep regulation in both flies and mammals [125][126][127]. Although there are numerous pieces of evidence regarding the roles of fly glial cells in circadian rhythmicity, little is known about Drosophila gliotransmitters in brains at present [128].…”

Sleep-promoting effects of threonine link amino acid metabolism in Drosophila neuron to GABAergic control of sleep drive

“…Conversely, glycine supplements improve sleep quality in a way distinct from traditional hypnotic drugs, minimizing deleterious cognitive problems or addiction (Bannai and Kawai, 2012; Yamadera et al, 2007). In fact, glycine or D-serine acts as a co-agonist of N-methyl-D-aspartate receptors (NMDARs) and promotes sleep through the sub-type of ionotropic glutamate receptors (Dai et al, 2019; Kawai et al, 2015; Tomita et al, 2015). Emerging evidence further supports the roles of amino acid transporters and metabolic enzymes in sleep regulation (Aboudhiaf et al, 2018; Sonn et al, 2018; Stahl et al, 2018).…”