title: Non-linear relationship between 5-HT transporter gene expression and frequency sensitivity of 5-HT signals.
abstract: Much evidence suggests that variation in expression of the 5-hydroxytryptamine (5-HT) transporter (5-HTT) is linked to risk of psychiatric illness, but the neurobiological basis of this association is uncertain. In this study, we investigated the impact of variation in 5-HTT expression on subsecond fluctuations in extracellular 5-HT concentrations ([5-HT](o) ). Stimulus-evoked [5-HT](o) was detected using fast-scan cyclic voltammetry at carbon-fibre microelectrodes in the substantia nigra in brain slices from 5-HTT knockout (KO) and 5-HTT over-expressing (OE) mice. Compared with wild-type (WT) controls, evoked [5-HT](o) was greater in KO and less in OE mice. In WT controls, evoked [5-HT](o) was frequency-sensitive; however, in both KO and OE mice, evoked [5-HT](o) showed a striking loss of frequency sensitivity. The latter was observed in WT mice after application of a 5-HTT blocker. These data show that while variation in 5-HTT expression modified the peak magnitude of [5-HT](o) evoked by any given stimulus in a gene dose dependent manner, there was a non-linear relationship between 5-HTT expression and frequency sensitivity. Overall, the findings suggest that variation in 5-HTT expression has a marked effect on frequency sensitivity which is a fundamental property of normal 5-HT transmission.
authors.affiliation: University Department of Pharmacology, Oxford, UK. katie.jennings@dpag.ox.ac.uk
authors.forename: Katie Ann
authors.initials: KA
authors.lastname: Jennings
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.forename: Trevor
authors.initials: T
authors.lastname: Sharp
authors.forename: Stephanie Jane
authors.initials: SJ
authors.lastname: Cragg
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D017711:Nonlinear Dynamics; D012701:Serotonin / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013997:Time Factors
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D012701:Serotonin