Fly into tranquility: GABA's role in Drosophila sleep

Abstract

Sleep is conserved across the animal kingdom, and Drosophila melanogaster is a prime model to understand its intricate circadian and homeostatic control. GABA (gamma-aminobutyric acid), the brain's main inhibitory neurotransmitter, plays a central role in sleep. This review delves into GABA's complex mechanisms of actions within Drosophila's sleep-regulating neural networks. We discuss how GABA promotes sleep, both by inhibiting circadian arousal neurons and by being a key neurotransmitter in sleep homeostatic circuits. GABA's impact on sleep is modulated by glia through astrocytic GABA recapture and metabolism. Interestingly, GABA can be coexpressed with other neurotransmitters in sleep-regulating neurons, which likely contributes to context-based sleep plasticity.

Figure 1:. GABA Synthesis, Transmission, and Metabolism in Drosophila

In Drosophila GABAergic neurons produce GABA via GAD1 (glutamic acid decarboxylase 1). GABA is transported into synaptic vesicles by vGAT (vesicular GABA transporter). Postsynaptic neurons can express various GABA-A and GABA-B receptors, which mediateshort-term and long-term effects of GABA on post-synaptic neuron activity, respectively. From the synaptic cleft, GABA is taken up by astrocytes via GAT (GABA transporter) to terminate signaling, and recycled through the GABA shunt and the TCA (TriCarboxylic Acid) cycle. The glutamine thus produced is returned to GABAergic neurons. Other abbreviations: SSA: Succinic SemiAldehyde; α-KG: α-KetoGlutarate, GS: Glutamine Synthetase. GABA-T: GABA Transaminase; RDL Resistance to Dieldrin Locus: LCCH3; Ligand-gated Chloride Channel Homolog 3; GRD: GABA and glycine-like Receptor of Drosophila; GABA-B R1–R3: GABA-B Receptors 1–3.

Figure 2:. GABA regulation of sleep via the circadian neural network

Diagram illustrating the different groups of circadian neurons in Drosophila melanogaster: the PDF-positive small and large ventral Lateral Neurons (sLNvs and lLNvs, in red), the PDF-negative 5th sLNvs (light grey), the dorsal Lateral Neurons (LNds, blue), the Lateral Posterior Neurons (LPNs, teal), the anterior and posterior Dorsal Neurons 1 (DN1as in red and DN1ps in green), the DN2s (blue) and DN3s (grey). Red emphasizes circadian neurons with well-characterized GABAergic regulation of their activity, which impacts sleep and arousal. GABA input is indicated in yellow. The DN1as are regulated by cold-activated TPN-II (Thermosensory Projection Neurons type II) GABAergic neurons, but the GABAergic neurons controlling lLNv activity remain unknown. Some LNds, DN1s and DN3s express RDL, but whether this expression impacts sleep is not yet established.

Figure 3:. GABA regulation of sleep via homeostatic circuits

Diagrams illustrating the role of GABA within the homeostasis sleep network of Drosophila. Panel A focuses on the Mushroom Bodies (MBs), panel B on the Central Complex, and panel C shows both systems as well as neurons mediating circadian input to these sleep circuits (green). In all three panels, GABAergic neurons are in yellow, their target in red or in shades of pink. The latter indicate that these neurons are also GABAergic. See main text for detail. A: PAM-DAN (Protocerebral Anterior Medial Dopaminergic Neurons) promote arousal via Kenyon Cellls (KCs) projecting to the γ and β’ lobes. PAM-DAN receive GABA input from unknown neurons. KC cells are also inhibited by DPM (Dorsal Paired Medial) and APL (Anterior Paired Lateral) neurons. MBONs: MB output neurons, which regulate among other behaviors sleep and arousal. Two GABAergic MBONs in each brain hemisphere promote sleep B: EB (Ellipsoid Neurons), dFB (dorsal Fan-shaped Bodies) and Helicon cells interact in a recurrent circuit. EB neurons also regulate sleep via the EPGs (Ellipsoid body-Protocerebral bridge-Gall neurons), while dFB neurons inhibit OAAs (Octopaminergic Output Arousal neurons). Temperature modulates the activity of GABAergic, Shaker positive (Sh+) neurons that synapse onto dFB neurons to regulate their activity. C: Tubu (TUbercular-BUlbar) neurons are regulated by sleep-promoting DN1 neurons, while PPM3 respond to circadian neurons promoting morning (PDF-positive sLNvs) and evening activity (5^th sLNv, LNds) [4]. NO (Noduli) and PB (Protocerebral Bridge) are also elements of the central complex.