Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice.
Anxiety and fear are normal emotional responses to threatening situations. In human anxiety disorders--such as panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, specific phobias and generalized anxiety disorder--these responses are exaggerated. The molecular mechanisms involved in the regulation of normal and pathological anxiety are mostly unknown. However, the availability of different inbred strains of mice offers an excellent model system in which to study the genetics of certain behavioural phenotypes. Here we report, using a combination of behavioural analysis of six inbred mouse strains with quantitative gene expression profiling of several brain regions, the identification of 17 genes with expression patterns that correlate with anxiety-like behavioural phenotypes. To determine if two of the genes, glyoxalase 1 and glutathione reductase 1, have a causal role in the genesis of anxiety, we performed genetic manipulation using lentivirus-mediated gene transfer. Local overexpression of these genes in the mouse brain resulted in increased anxiety-like behaviour, while local inhibition of glyoxalase 1 expression by RNA interference decreased the anxiety-like behaviour. Both of these genes are involved in oxidative stress metabolism, linking this pathway with anxiety-related behaviour.
Hovatta
Iiris
I
The Salk Institute for Biological Studies, Laboratory of Genetics, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Tennant
Richard S
RS
Helton
Robert
R
Marr
Robert A
RA
Singer
Oded
O
Redwine
Jeffrey M
JM
Ellison
Julie A
JA
Schadt
Eric E
EE
Verma
Inder M
IM
Lockhart
David J
DJ
Barlow
Carrolee
C
D000818:Animals; D001007:Anxiety / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D001921:Brain / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005980:Glutathione Reductase / Q000235:genetics / Q000378:metabolism*; D007791:Lactoylglutathione Lyase / Q000235:genetics / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018384:Oxidative Stress / Q000235:genetics; D010641:Phenotype; D014161:Transduction, Genetic
D005980:Glutathione Reductase; D007791:Lactoylglutathione Lyase