Substrates for Neuronal Cotransmission With Neuropeptides and Small Molecule Neurotransmitters in Drosophila

Abstract

It has been known for more than 40 years that individual neurons can produce more than one neurotransmitter and that neuropeptides often are colocalized with small molecule neurotransmitters (SMNs). Over the years much progress has been made in understanding the functional consequences of cotransmission in the nervous system of mammals. There are also some excellent invertebrate models that have revealed roles of coexpressed neuropeptides and SMNs in increasing complexity, flexibility, and dynamics in neuronal signaling. However, for the fly Drosophila there are surprisingly few functional studies on cotransmission, although there is ample evidence for colocalization of neuroactive compounds in neurons of the CNS, based both on traditional techniques and novel single cell transcriptome analysis. With the hope to trigger interest in initiating cotransmission studies, this review summarizes what is known about Drosophila neurons and neuronal circuits where different neuropeptides and SMNs are colocalized. Coexistence of neuroactive substances has been recorded in different neuron types such as neuroendocrine cells, interneurons, sensory cells and motor neurons. Some of the circuits highlighted here are well established in the analysis of learning and memory, circadian clock networks regulating rhythmic activity and sleep, as well as neurons and neuroendocrine cells regulating olfaction, nociception, feeding, metabolic homeostasis, diuretic functions, reproduction, and developmental processes. One emerging trait is the broad role of short neuropeptide F in cotransmission and presynaptic facilitation in a number of different neuronal circuits. This review also discusses the functional relevance of coexisting peptides in the intestine. Based on recent single cell transcriptomics data, it is likely that the neuronal systems discussed in this review are just a fraction of the total set of circuits where cotransmission occurs in Drosophila. Thus, a systematic search for colocalized neuroactive compounds in further neurons in anatomically defined circuits is of interest for the near future.

Drosophila carboxypeptidase D (SILVER) is a key enzyme in neuropeptide processing required to maintain locomotor activity levels and survival rate

“…In both the larval and adult CNS, a large number of neurons innervating basically all neuropiles expressed svr PG33 ‐Gal4‐driven GFP (Figure a). This is in line with the idea that many Drosophila neurons express peptide co‐transmitters (Nässel, ). Due to the broad expression, it was impossible to identify specific arborisation patterns except for the tightly packed Kenyon cells with their parallel projections in the mushroom bodies (Figure a–c).…”

Drosophilacarboxypeptidase D (SILVER) is a key enzyme in neuropeptide processing required to maintain locomotor activity levels and survival rate

“…In both the larval and adult CNS, a large number of neurons innervating basically all neuropiles expressed svr PG33 -Gal4-driven GFP (Figure 4a). This is in line with the idea that many Drosophila neurons express peptide co-transmitters (Nässel, 2018).…”

A single-cell transcriptomic atlas of the adultDrosophilaventral nerve cord

“…We identified 28 neuropeptides that are expressed in at least one cell, at a 440 20 level of 10 or more transcripts per cell ( Figure 8A). Some neuropeptides are known to be 441 co-expressed with FANs, where they serve to increase signaling flexibility within neural 442 networks (Croset et al, 2018;Nässel, 2018;Nusbaum et al, 2017). We found that in the 443 VNC some neuropeptide genes are predominantly co-expressed with particular FANs, e.g.…”

“…High-level expression of neuropeptides 653 in this cluster is consistent with features of neurosecretory biology. Neuropeptides are 654 often produced by small numbers of cells, yet they can be broadly released and by volume 655 transmission and/or secretion into the hemolymph act at a distance to modulate disparate 656 neural circuits, physiological functions and behaviors (Nässel, 2018). The extraordinarily 657 high-level expression of pre-pro-neuropeptide genes in these cells suggests that 658 producing these molecules presents a considerable burden.…”