The expression of the cocaine-sensitive serotonin transporter (SerT) is regulated in a complex manner in the developing central nervous system (CNS). Mutations that alter expression of SerT are associated with a number of human mental illnesses. Here we describe a set of experiments in the relatively simple fly CNS that test the role of certain genes in regulating SerT. In addition, we also propose to examine the effects of altering SerT expression on serotonergic cellular anatomy. Our previous experiments showed that the axon guidance molecule robo2 regulates SerT expression via the transcription factor eagle (eg). Here we test whether the cytoplasmic tyrosine kinase abl mediates robo2 signaling to eg. Our preliminary data indicate that members of the FGF signaling pathway function to inhibit SerT activity. In FGF, FGF-receptor, pointed (pnt) andros mutants, precocious SerT activity appears during embryonic development. Here we propose to test where and when these molecules function to attenuate SerT activity. Our working model is that the activation of embryonic SerT expression is a balance between robo2/eg induction and FGF/pnt inhibition. This balance is further revealed by the fact that the phenotype of each single mutant is suppressed in a pnt/eg double mutant. We therefore propose to examine how the balance of robo2 and FGF signaling regulates SerT. While the robo2/eg and FGF/pnt pathways seem to function during initial SerT onset early in development we will also test whether these same molecules continue to function as regulators in the CNS of the behaving larva. For this we will use timed expression of components of these pathways to test for later function. Extracellular serotonin levels, as regulated by SerT, have been hypothesized to regulate serotonergic synapse formation. We have developed a method to quantify serotonergic synaptic varicosities in the CNS. We will use this approach to first test the direct effects of altering SerT and serotonin levels on varicosities. We will then test the effects of altering genes that regulate SerT and serotonin. The long-term goal of this research is to further understand the regulation and function of this clinically relevant molecule.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA020942-07
Application #
7090106
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Wu, Da-Yu
Project Start
1997-12-01
Project End
2010-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
7
Fiscal Year
2006
Total Cost
$219,631
Indirect Cost
Name
University of Virginia
Department
Neurosciences
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Borue, Xenia; Condron, Barry; Venton, B Jill (2010) Both synthesis and reuptake are critical for replenishing the releasable serotonin pool in Drosophila. J Neurochem 113:188-99
Daubert, Elizabeth A; Heffron, Daniel S; Mandell, James W et al. (2010) Serotonergic dystrophy induced by excess serotonin. Mol Cell Neurosci 44:297-306
Daubert, Elizabeth A; Condron, Barry G (2010) Serotonin: a regulator of neuronal morphology and circuitry. Trends Neurosci 33:424-34
Borue, Xenia; Cooper, Stephanie; Hirsh, Jay et al. (2009) Quantitative evaluation of serotonin release and clearance in Drosophila. J Neurosci Methods 179:300-8
Vickrey, Trisha L; Condron, Barry; Venton, B Jill (2009) Detection of endogenous dopamine changes in Drosophila melanogaster using fast-scan cyclic voltammetry. Anal Chem 81:9306-13
Chen, John; Condron, Barry G (2009) Drosophila serotonergic varicosities are not distributed in a regular manner. J Comp Neurol 515:441-53
Chen, John; Condron, Barry G (2008) Branch architecture of the fly larval abdominal serotonergic neurons. Dev Biol 320:30-8
Borue, Xenia; Chen, John; Condron, Barry G (2007) Developmental effects of SSRIs: lessons learned from animal studies. Int J Dev Neurosci 25:341-7
Sykes, Paul A; Condron, Barry G (2005) Development and sensitivity to serotonin of Drosophila serotonergic varicosities in the central nervous system. Dev Biol 286:207-16