Serotonin functions as a bidirectional guidance molecule regulating growth cone motility
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
Serotonin functions as a bidirectional guidance molecule regulating growth cone motility Silvia Vicenzi1 · Lisa Foa2 · Robert J. Gasperini1 Received: 29 June 2020 / Revised: 14 August 2020 / Accepted: 21 August 2020 © Springer Nature Switzerland AG 2020
Abstract The neurotransmitter serotonin has been implicated in a range of complex neurological disorders linked to alterations of neuronal circuitry. Serotonin is synthesized in the developing brain before most neuronal circuits become fully functional, suggesting that serotonin might play a distinct regulatory role in shaping circuits prior to its function as a classical neurotransmitter. In this study, we asked if serotonin acts as a guidance cue by examining how serotonin alters growth cone motility of rodent sensory neurons in vitro. Using a growth cone motility assay, we found that serotonin acted as both an attractive and repulsive guidance cue through a narrow concentration range. Extracellular gradients of 50 µM serotonin elicited attraction, mediated by the serotonin 5-HT2a receptor while 100 µM serotonin elicited repulsion mediated by the 5-HT1b receptor. Importantly, high resolution imaging of growth cones indicated that these receptors signalled through their canonical pathways of endoplasmic reticulum-mediated calcium release and cAMP depletion, respectively. This novel characterisation of growth cone motility in response to serotonin gradients provides compelling evidence that secreted serotonin acts at the molecular level as an axon guidance cue to shape neuronal circuit formation during development. Keywords Serotonin · Growth cone · Axon guidance · Guidance cue · Circuit development · Axon pathfinding Abbreviations 5-HT 5-hydroxytryptamine; serotonin CNS Central nervous system DRG Dorsal root ganglia SNM Sensory neuron medium DMEM Dulbecco’s Modified Eagle’s Medium BDNF Brain-derived neurotrophic factor sema-3a Semaphorin-3A ROI Region of interest PFA Paraformaldehyde PBS Phosphate buffered saline PLC Phospholipase-C ER Endoplasmic reticulum Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-020-03628-2) contains supplementary material, which is available to authorized users. * Robert J. Gasperini [email protected] 1
School of Medicine, University of Tasmania, Hobart, Australia
School of Psychological Sciences, University of Tasmania, Hobart, Australia
2
IP3 Inositol triphosphate SERCA Sarco-endoplasmic reticulum ATPase VGCCs Voltage-gated calcium channels SOCE Store operated calcium entry
Introduction Serotonin (5-hydroxytryptamine, 5-HT) is a crucial neurotransmitter with a range of nervous system functions including modulation of cognition, sleep, decision-making and attention [1, 2] in the adult brain. Serotonin also regulates early central nervous system (CNS) development including neuronal migration, proliferation, differentiation and synaptogenesis [3–5]. In neuronal circuit development, extra
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