Pallidin function in drosophila surface glia regulates sleep and is dependent on amino acid availability

Abstract

The Pallidin protein is a component of a multimeric complex named the Biogenesis of Lysosome-related Organelles Complex 1 (BLOC1) that regulates specific endosomal function and transmembrane protein trafficking in many different cell types. In the brain, defective BLOC1 function has been linked to schizophrenia, a neuropsychiatric disorder with highly prevalent sleep disruptions, and to impaired cognitive abilities in healthy subjects. In animal models, defective BLOC1 function also impairs behavior, memory, neurotransmission systems and metabolism. This growing body of experimental evidence suggest an involvement of BLOC1 in sleep/wake regulation. Here, we used Drosophila molecular genetics and conditional, cell-type specific knockdown strategy to address this question. We show that down-regulation of a central subunit of BLOC1, Pallidin, in the surface glia, the Drosophila equivalent of the blood brain barrier, is sufficient to reduce, fragment and delay nighttime sleep at the adult stage and in a circadian clock dependent manner. Other members of the BLOC1 complex appear to be involved in this surface glia-dependent sleep regulation. In agreement with a BLOC1 involvement in amino acid transport, down-regulation of the Large neutral Amino acid Transporter 1 (LAT1)-like transporters JhI-21 and minidiscs, phenocopy the down-regulation of pallidin. Similar results were obtained by inhibiting the TOR amino acid signaling pathway. Supplementing food with essential amino acids normalizes the sleep/wake phenotypes of pallidin and JhI-21 down-regulation. Furthermore, we identify a role for pallidin in the subcellular trafficking of JhI-21 in surface glial cells. Finally, we provide evidence that Pallidin function in surface glia is required for GABAergic neurons activation involved in promoting sleep. Taken together, these data identify a novel role for BLOC1 that, through LAT1-like transporters subcellular trafficking modulates essential amino acid availability and GABAergic sleep/wake regulation.