LAT1-like transporters regulate dopaminergic transmission and sleep in Drosophila

Abstract

Amino acid transporters are involved in functions reportedly linked to the sleep/wake cycle: neurotransmitter synthesis and recycling, the regulation of synaptic strength, protein synthesis, and energy metabolism. In addition, the existence of bidirectional relationships among extracellular content, transport systems, and sleep/wake states is receiving emerging support. Nevertheless, the connection between amino acid transport and sleep/wake regulation remains elusive. To address this question, we used Drosophila melanogaster and investigated the role of LAT1 (large neutral amino acid transporter 1) transporters. We show that the two Drosophila LAT1-like transporters: Juvenile hormone Inducible-21 and minidiscs (Mnd) are required in dopaminergic neurons for sleep/wake regulation. Down-regulating either gene in dopaminergic neurons resulted in higher daily sleep and longer sleep bout duration during the night, suggesting a defect in dopaminergic transmission. Since LAT1 transporters can mediate in mammals the uptake of L-DOPA, a precursor of dopamine, we assessed amino acid transport efficiency by L-DOPA feeding. We find that downregulation of JhI-21, but not Mnd, reduced the sensitivity to L-DOPA as measured by sleep loss. JhI-21 downregulation also attenuated the sleep loss induced by continuous activation of dopaminergic neurons. Since LAT1 transporters are known to regulate target of rapamycin (TOR) signaling, we investigated the role of this amino acid sensing pathway in dopaminergic neurons. Consistently, we report that TOR activity in dopaminergic neurons modulates sleep/wake states. Altogether, this study provides evidence that LAT1-mediated amino acid transport in dopaminergic neurons is playing a significant role in sleep/wake regulation and is providing several entry points to elucidate the role of nutrients such as amino acids in sleep/wake regulation.

A conserved role for sleep in supporting spatial learning inDrosophila

“…Dopamine was increased by feeding flies the dopamine precursor Levodopa (L-Dopa) 54,55 . As seen in Figure 7A, feeding 20day old flies L-DOPA disrupted nighttime sleep as previously reported 56,57 . Importantly, spatial learning was restored in 20-day old, L-Dopa fed flies compared to their age-matched vehicle-fed siblings ( Figure 7B).…”

The effect of the endosymbiont Wolbachia on the behavior of insect hosts

“…Furthermore, JH Inducible-21 (JHI-21) has been reported to be required for sleep/wake regulation, since downregulation of JhI-21 in dopaminergic neurons reduced the sensitivity to L-DOPA, thus leading to an increase in daily sleep and sleep bout duration during the night. (Aboudhiaf et al, 2018). Correspondingly, our previous work found that Wolbachia could stimulate the JH signaling pathway in male Drosophila (Liu et al, 2014).…”

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

“…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). In particular, we have demonstrated that starvation induces the expression of metabolic enzymes for serine biosynthesis in Drosophila brains, and elevates free serine levels to suppress sleep via cholinergic signaling (Sonn et al, 2018).…”