Abstract
Modifying serotonin (5-HT) abundance in the embryonic mouse brain disrupts the precision of sensory maps formed by thalamocortical axons (TCAs), suggesting that 5-HT influences their growth. We investigated the mechanism by which 5-HT influences TCAs during development. 5-HT1B and 5-HT1D receptor expression in the fetal forebrain overlaps with that of the axon guidance receptors DCC and Unc5c. In coculture assays, axons originating from anterior and posterior halves of the embryonic day 14.5 dorsal thalamus responded differently to netrin-1, reflecting the patterns of DCC and Unc5c expression. 5-HT converts the attraction exerted by netrin-1 on posterior TCAs to repulsion. Pharmacological manipulation of 5-HT1B/1D receptors and intracellular cAMP showed the signaling cascade through which this modulation occurs. An in vivo correlate of altered TCA pathfinding was obtained by transient manipulation of 5-HT1B/1D receptor expression abundance in the dorsal thalamus by in utero electroporation. These data demonstrate that serotonergic signaling has a previously unrecognized role in the modulation of axonal responsiveness to a classic guidance cue.
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Acknowledgements
We thank J. Wu and H.H. Wu for technical help and comments, and K.L. Eagleson and G. Stanwood for comments on the manuscript. The work was supported in part by US National Institute of Mental Health grant MH65299 and US National Institute of Child Health and Human Development P30HD15052 to P.L.
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A.B. participated in the design of the project, the writing of the manuscript and conducted and analyzed the experiments. M.T. conducted and participated in the analyses of crucial in utero electroporation experiments and helped to write the manuscript. L.W. performed the statistical analyses. P.R. contributed to the in vivo experiments and helped to write the manuscript. P.L. contributed to the design of the experiments, interpretation of results and writing of the manuscript.
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Supplementary information
Supplementary Fig. 1
Putative 5-HT signaling in development. (PDF 496 kb)
Supplementary Fig. 2
Putative 5-HT signaling in development. (PDF 892 kb)
Supplementary Fig. 3
Quantification of netrin-G1 immunofluorescent intensity at E18.5 on the control and electroporated side of brains electroporated at E12.5. (PDF 170 kb)
Supplementary Fig. 4
Pathways of TCAs from anterior and posterior DT in horizontal sections at E14.5. (PDF 1312 kb)
Supplementary Fig. 5
Anterior-posterior positioning of TCAs in the IC is associated with their medial-lateral, rather than anterior-posterior, origin in the DT. (PDF 1262 kb)
Supplementary Fig. 6
Comparison between Gbx2 and Unc5c expression patterns in dorso-ventral series of horizontal sections through the E14.5 DT. (PDF 489 kb)
Supplementary Fig. 7
Schematic representation of TCA pathfinding. (PDF 63 kb)
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Bonnin, A., Torii, M., Wang, L. et al. Serotonin modulates the response of embryonic thalamocortical axons to netrin-1. Nat Neurosci 10, 588–597 (2007). https://doi.org/10.1038/nn1896
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DOI: https://doi.org/10.1038/nn1896
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