Serotonin’s Axon Guidance Switch

Science's STKE  01 May 2007:
Vol. 2007, Issue 384, pp. tw150
DOI: 10.1126/stke.3842007tw150

Alterations in signaling by the neurotransmitter serotonin (also called 5-hydroxytryptamine or 5-HT) are associated with psychiatric illnesses, including anxiety disorders and depression. Such effects may reflect abnormal signaling at synapses in adult brain or changes in brain development, during which serotonin is also present and influences pathfinding by thalamocortical neurons. Bonnin et al. provide mechanistic insight into how changes in serotonin signals can disrupt axon migration. In cultured explants from the dorsal thalamus of mice, axons are normally attracted to HEK-293 cells in the same culture that are engineered to express the axon guidance protein netrin-1. But when the authors treated the explants with serotonin, the axons reversed their response to netrin-1 and were repelled from the cells producing the netrin-1. This response was caused by decreased synthesis of the second messenger cAMP (adenosine 3′,5′-monophosphate) in the serotonin-stimulated dorsal thalamus neurons. Pharmacological inhibition of the cAMP-dependent protein kinase could reproduce the effect of serotonin, and activation of the kinase blocked the serotonin effect. To show the importance of this effect in vivo, the authors used targeted electroporation of the developing brain in mouse embryos in the mother’s uterus, thereby causing the cells of the dorsal thalamus to express more serotonin receptors (to enhance signaling) or to express small interfering RNA to the receptors (to limit serotonin signaling). At the same time, the authors introduced a plasmid encoding a fluorescent marker protein that allowed them to trace the growth of the transfected axons. Increasing and decreasing serotonin signaling produced opposite effects, and both caused abnormal migration trajectories of the thalamus axons. Thus the authors propose that developmental abnormalities in serotonin signaling--either too much or too little--may alter the circuitry of thalamocortical axons and thus alter brain functions that later contribute to mental health disorders.

A. Bonnin, M. Torii, L. Wang, P. Rakic, P. Levitt, Serotonin modulates the response of embryonic thalamocortical axons to netrin-1. Nat. Neurosci. 10, 588-597 (2007). [PubMed]