Abnormal anxiety-related behavior in serotonin transporter null mutant mice: the influence of genetic background.
Serotonin transporter (5-HTT) null mutant mice provide a model system to study the role genetic variation in the 5-HTT plays in the regulation of emotion. Anxiety-like behaviors were assessed in 5-HTT null mutants with the mutation placed on either a B6 congenic or a 129S6 congenic background. Replicating previous findings, B6 congenic 5-HTT null mutants exhibited increased anxiety-like behavior and reduced exploratory locomotion on the light <--> dark exploration and elevated plus-maze tests. In contrast, 129S6 congenic 5-HTT null mutant mice showed no phenotypic abnormalities on either test. 5-HTT null mutants on the 129S6 background showed reduced 5-HT(1A) receptor binding (as measured by quantitative autoradiography) and reduced 5-HT(1A) receptor function (as measured by 8-OH-DPAT-induced hypothermia). These data confirm that the 5-HTT null mutation produced alterations in brain 5-HT function in mice on the 129S6 background, thereby discounting the possibility that the absence of an abnormal anxiety-like phenotype in these mice was due to a suppression of the mutation by 129 modifier genes. Anxiety-like behaviors in the light <--> dark exploration and elevated plus-maze tests were significantly higher in 129S6 congenic +/+ mice as compared to B6 congenic +/+ mice. This suggests that high baseline anxiety-like behavior in the 129S6 strain might have precluded detection of the anxiety-like effects of the 5-HTT null mutation on this background. Present findings provide further evidence linking genetic variation in the 5-HTT to abnormalities in mood and anxiety. Furthermore, these data highlight the utility of conducting behavioral phenotyping of mutant mice on multiple genetic backgrounds.
Holmes
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A
Laboratory of Behavioral Neuroscience, National Institute of Mental Health, Building 10, Room 4D11, Bethesda, MD 20892-1375, USA. aholmes@intra.nimh.nih.gov
Lit
Q
Q
Murphy
D L
DL
Gold
E
E
Crawley
J N
JN
D000818:Animals; D001007:Anxiety / Q000235:genetics*; D001008:Anxiety Disorders / Q000235:genetics*; D001923:Brain Chemistry / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology*; D005260:Female; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins; D019683:Penetrance; D050486:Serotonin Plasma Membrane Transport Proteins
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse