Insertion mutation at the C-terminus of the serotonin transporter disrupts brain serotonin function and emotion-related behaviors in mice.
The 5-hydroxytryptamine transporter (5-HTT) regulates 5-hydroxytryptamine (5-HT) neurotransmission by removing 5-HT from the synaptic cleft. Emerging evidence from clinical and genetic studies implicates the 5-HTT in various neuropsychiatric conditions, including anxiety and depression. Here we report that a 5-HTT null mutant mouse line was generated by gene trapping that disrupted the sequence encoding the C-terminus of 5-HTT. This mutation resulted in significant reduction of 5-HTT mRNA and loss of 5-HTT protein. Brain levels of 5-HT and its major metabolite, 5-hydroxyindoleacetic acid, were markedly decreased in C-terminus 5-HTT -/- mice, while 5-HT uptake or 5-HT content in platelets was absent. Behavioral phenotyping showed that C-terminus 5-HTT -/- mice were normal on a screen for gross behavioral, neurological, and sensory functions. In the tail suspension test for depression-related behavior, C-terminus 5-HTT -/- mice showed increased immobility relative to their +/+ controls. By comparison, a previously generated line of 5-HTT -/- mice lacking exon 2, encoding the N-terminus of the 5-HTT, showed abnormally high immobility in response to repeated, but not acute, exposure to the tail suspension test. In a novel, brightly-lit open field, both C-terminus 5-HTT -/- mice and N-terminus 5-HTT -/- mice displayed decreased center time and reduced locomotor activity compared with their +/+ controls. Both mutant lines buried significantly fewer marbles than their +/+ controls in the marble burying test. These findings further demonstrate the neurobiological functions of the 5-HTT and add to a growing literature linking genetic variation in 5-HTT function with emotional abnormalities.
Zhao
S
S
Lexicon Genetics Incorporated, 8800 Technology Forest Place, The Woodlands, TX 77381, USA. szhao@lexgen.com
Edwards
J
J
Carroll
J
J
Wiedholz
L
L
Millstein
R A
RA
Jaing
C
C
Murphy
D L
DL
Lanthorn
T H
TH
Holmes
A
A
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D001923:Brain Chemistry / Q000235:genetics; D015283:Citalopram / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004644:Emotions / Q000502:physiology*; D005106:Exploratory Behavior / Q000502:physiology; D019417:Hindlimb Suspension / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009154:Mutation; D010446:Peptide Fragments / Q000172:deficiency; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D012701:Serotonin / Q000493:pharmacokinetics / Q000502:physiology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry / Q000172:deficiency*; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics; D014316:Tritium / Q000493:pharmacokinetics
D015283:Citalopram; D010446:Peptide Fragments; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014316:Tritium