Just the Right Amount of Guidance

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Science  11 May 2007:
Vol. 316, Issue 5826, pp. 801
DOI: 10.1126/science.316.5826.801c

Dysfunctional signaling by the neurotransmitter serotonin (5-HT) is associated with psychiatric illnesses such as anxiety disorders and depression. These conditions may reflect abnormal signaling at synapses in the adult brain or changes that have occurred during brain development, when serotonin is 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 that have been engineered to express the axon guidance protein netrin-1. But when the explants were treated with serotonin, the axons reversed their response and were repelled from cells producing netrin-1. This response was caused by decreased synthesis of the second messenger cAMP in the serotonin-stimulated dorsal thalamus neurons. Pharmacological inhibition of the cAMP-dependent protein kinase could reproduce the effect of serotonin, whereas activation of the kinase blocked the serotonin effect. To show the importance of this effect in vivo, the authors used targeted electroporation in developing mouse embryos, thereby causing the cells of the dorsal thalamus to express either more serotonin receptors (to enhance signaling) or fewer receptors (to limit signaling). Increasing and decreasing serotonin signaling produced opposite effects, and both manipulations 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 may contribute to mental health disorders. — LBR

Nat. Neurosci. 10, 588 (2007).

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