A polymorphic glucocorticoid receptor in a mouse population may explain inherited altered stress response and increased anxiety-type behaviors.

A polymorphic glucocorticoid receptor (GR(Qn)) with an expanded CAG track and two silent mutations, when compared with the sequence of other isoform (GR(wt)), is found in two outbred mouse lines that were produced by selection for high (SH) or low (SL) stress response from high or low heat loss lines of mice, respectively. The GR(Qn) allele, which is also found in 5 of 16 commonly used inbred mouse lines, had a much higher frequency in SL mice; the GR(wt/wt) was found only in the SH line. Both GR(Qn/Qn) and GR(wt/Qn) mice had a much weaker corticosterone response to stress than the GR(wt/wt) mice. Assessment of open field activity revealed that GR(Qn/Qn) and GR(wt/Qn) mice exhibited significantly lower velocity and locomotor activity, less time in the center, and much longer duration in corner zones than the GR(wt/wt) mice. The increased anxiety-type behaviors of the GR(Qn/Qn) and GR(wt/Qn) mice were confirmed by the "elevated plus maze" test in which GR(Qn/Qn) and GR(wt/Qn) mice spent significantly less time in the "open arm" and longer duration in the "closed arm," than GR(wt/wt) mice. These results suggest this GR polymorphism plays a role in complex mechanisms leading to lower corticosterone response to stress, and may also be associated with decreased locomotive and increased anxiety-type behaviors in mice.