Research resource: loss of the steroid receptor coactivators confers neurobehavioral consequences

Abstract

Steroid receptor coactivators (SRCs) are important transcriptional modulators that regulate nuclear receptor and transcription factor activity to adjust transcriptional output to cellular demands. Highlighting their pleiotropic effects, dysfunction of the SRCs has been found in numerous pathologies including cancer, inflammation, and metabolic disorders. The SRC family is expressed strongly in the brain including the hippocampus, cortex, and hypothalamus. Studies focusing on the effect of SRC loss using congenic SRC knockout mice (SRC(-/-)) are limited in number, yet strongly indicate that the SRCs play important roles in regulating reproductive behavior, development, and motor coordination. To better understand the unique functions of the SRCs, we performed a neurobehavioral test battery focusing on anxiety and exploratory behaviors, motor coordination, sensorimotor gating, and nociception in both male and female null mice and compared them with their wild-type (WT) littermates. Results from the test battery reveal a role for SRC1 in motor coordination. Additionally, we found that SRC1 regulates anxiety responses in SRC1(-/-) male and female mice, and nociception sensitivity in SRC1(-/-) male but not female mice. By comparison, SRC2 regulates anxiety response with SRC2(-/-) females showing decreased anxiety in novel environments, as well as increased exploratory behavior in the open field compared with WT littermates. Additionally, SRC2(-/-) males were shown to have deficits in sensorimotor gating. Loss of SRC3 also shows sex differences in anxiety and exploratory behaviors. In particular, SRC3(-/-) female mice have increased anxiety and reduced exploratory activity and impairments in prepulse inhibition, whereas SRC3(-/-) male mice show no significant behavioral differences. In both genders, ablation of SRC3 decreases nocifensive behaviors. Collectively, these resource data suggest that loss of the SRCs results in behavioral phenotypes, underscoring the importance of understanding both the general and gender-based activity of SRCs in the brain.

Figure 1.

SRC Expression throughout the Brain. A–C, SRC expression in WT brain as measured by in situ hybridization (ISH) in coronal sections from WT mice for SRC1 (A), SRC2 (B), and SRC3 (C), respectively.

Figure 2.

Analysis of SRC Ablation in the EPM. A–C, Total distance traveled and total entries made in the EPM in WT and SRC^−/− male and female littermate mice. A, SRC1^−/− male mice travel greater distances and have increased entries in the EPM. B, SRC2^−/− female mice have increased total distance traveled than WT female mice. C, SRC3^−/− females travel less distance and cross fewer entries than WT female mice. Mean ± SEM; *, P < .05.

Figure 3.

Analysis of SRC Ablation in the OFA. A–C, Distance traveled, center distance traveled to total distance traveled ratio, number of movements, and number of rears measured during the OFA in WT and SRC^−/− genotypes in male and female littermate mice. A, SRC1^−/− female mice have decreased center/total distance traveled. B, SRC2^−/− female mice have increased total distance traveled, increased center/total distance ratio, and increased movements compared with WT littermates in the OFA. C, SRC3^−/− female mice have decreased total distance traveled, decreased center to total distance ratio, and decreased movements and rearing behavior. Mean ± SEM; *, P < .05.

Figure 4.

Analysis of SRC^−/− Mice Performance in Motor Coordination. A–C, The latency to fall during 8 trials on the rotarod for SRC^−/− genotypes and respective WT male and female littermates were measured. A, WT and SRC1^−/− female mice showed a slight decrease in the time spent on the rotarod. B, WT and SRC1^−/− male mice had a modest increase in latency to fall from the rotarod. C, WT and SRC2^−/− female mice show no differences on the rotarod. D, SRC2^−/− male mice show increased ability to perform on the rotarod compared with WT mice. E, WT and SRC3^−/− female mice show no differences on the rotarod. F, SRC3^−/− male mice show a decrease in latency to fall from the rotarod. Mean ± SEM; *, P < .05.

Figure 5.

Sensorimotor Gating and Acoustic Startle Response in the SRC^−/− Mice. A–F, Sensorimotor gating and acoustic startle response tested through PPI in WT and SRC^−/− male and female littermates. A–D, PPI and acoustic startle response in WT and SRC1^−/− female (A and B) and male mice (C and D) show no differences. E and F, PPI and acoustic startle response in WT and SRC2^−/− female mice show no differences. G and H, Decreased PPI and acoustic startle response were observed in SRC2^−/− male mice compared with WT. I and J, Decreased PPI with no change in acoustic startle response in SRC3^−/− female mice compared with WT mice. K and L, No changes observed between WT and SRC3^−/− male mice in PPI (K), whereas SRC3^−/− male mice showed a decrease in the acoustic startle response (L). Mean ± SEM; *, P < .05.

Figure 6.

Nociception test in SRC^−/− mice. A–C, WT and SRC^−/− male and female mice were placed on a hot plate at 55°C, and the latency to lift, shake, or lick their hind paws was measured. A, SRC1^−/− male mice show an increased sensitivity to the hot plate with no changes observed between WT and SRC1^−/− female mice. B, SRC2^−/− female mice have decreased sensitivity to the hot plate, with no changes observed for SRC2^−/− males. C, SRC3^−/− male and SRC3^−/− female mice display decreased latency to the hot plate. Mean ± SEM; *, P < .05.