Serotonin modulates the response of embryonic thalamocortical axons to netrin-1.
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-HT(1B) and 5-HT(1D) 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-HT(1B/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-HT(1B/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.
Bonnin
Alexandre
A
Department of Pharmacology, Vanderbilt University, 465 21st Ave. South, Nashville, Tennessee 37232, USA.
Torii
Masaaki
M
Wang
Lilly
L
Rakic
Pasko
P
Levitt
Pat
P
D000344:Afferent Pathways / Q000166:cytology / Q000196:embryology; D000367:Age Factors; D000818:Animals; D001369:Axons / Q000378:metabolism*; D002461:Cell Line, Transformed; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D018274:Electroporation / Q000379:methods; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D017403:In Situ Hybridization / Q000379:methods; D066298:In Vitro Techniques; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000378:metabolism*; D000075388:Netrin-1; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D013788:Thalamus / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D008164:Luminescent Proteins; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D034741:RNA, Small Interfering; D011985:Receptors, Serotonin; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D012701:Serotonin