The goal of the research is to determine the role that serotonin (5-HT), a biogenic amine that appears very early in brain development and whose levels can be markedly influenced by both prescription medications and drugs of abuse, plays in the development of the mammalian retinotectal projections. Recent results have suggested that 5-HT profoundly influences the postnatal refinement of retinotectal axon arbors and that this may be a result of 5-HT 1B receptor-mediated effects of this amine on activity-dependent mechanisms known to be involved in this process. Moreover, work in other systems has suggested that 5-HT might also influence the initial collateralization of retinotectal axons. The proposed experiments will further elucidate the role of 5-HT in retinotectal development by: 1) Determining whether the retinotectal projection is altered when 5-HT is directly applied to the superior colliculus (SC) throughout development. The pI will place slow release polymer chips impregnated with 5-HT over the SC for the first 3 weeks of life and then use anterograde tracing techniques to assess the organization of retinotectal projections. 2) Determining whether 5-HT influences retinotectal axon refinement through effects of this amine on synaptic transmission. The principal investigator will carry out in vivo experiments to determine whether the apparently enhanced refinement of the uncrossed retinotectal projection associated with a reduced 5-HT concentration in SC during development can be blocked by application of TTX directly to the SC. 3) Determining whether the activity-dependent effects of 5-HT on developing retinal axons are mediated by the 5-HT1B receptor. The principal investigator will use radioligand binding to determine when 5-HT1B receptors first appear in the developing SC and define the elements which express them. They will also carry out in vitro physiological experiments to define the effects of 5-HT on retinotectal transmission in developing hamsters and to determine the pharmacologic profile (s) of the receptor(s) mediating these actions. They will evaluate the development of retinotectal projections in transgenic mice lacking the 5-HT1B receptor. 4) Determining whether altered 5-HT concentration influences the initial collateralization of retinotectal axons in vivo and whether increased concentrations of this amine influence axonal outgrowth from identified ganglion cells in vitro.
