Damian G. Zuloaga ¹, John A. Morris ², Cynthia L. Jordan ¹, ², S. Marc Breedlove ¹, ² ¹Department of Psychology; ² Neuroscience Program Michigan State University, East Lansing, MI Introduction Methods Significance Results Summary Acknowledgments 252 Prepulse Inhibition is Reduced in Mice with the Testicular Feminization Mutation Sensorimotor gating is the ability to inhibit or gate sensory information. Deficits in sensorimotor gating are found in people with schizophrenia and it is believed that this deficit may result in symptoms such as delusions, hallucinations, and disruptions in thought. Sensorimotor gating is assessed in humans and rodents by measuring the prepulse inhibition (PPI) to the acoustic startle response in which the fast twitch muscle response to a loud acoustic stimulus is reduced if it is preceded by a weak acoustic tone. Hormones have been shown to play a role in regulating sensorimotor gating. Sex differences in PPI have been reported in humans and some strains of mice and rats and PPI has also been shown to vary in response to circulating estrogen levels. Recent evidence also suggests that testosterone may play a role in regulating PPI, however the hormone receptor type involved in this process is unknown. In order to investigate the role of the androgen receptor (AR) in PPI we tested mice with the testicular feminization mutation (TFM) which renders the androgen receptor nonfunctional. TFM male mice showed significantly reduced PPI compared to wild type males and also tended to show lower PPI compared to wild type females, although differences were not significant. TFM males show reduced PPI compared to males at all prepulse decibels with the greatest difference found at the weakest prepulse. Sex differences in PPI were also found in which males showed greater PPI than females consistently across different prepulses. The acoustic startle response was also reduced in TFM males compared to wild type males. Their startle responses were similar to those of females. Supported by The MSU Foundation and NIH NS & MH58703 Figure 1. Prepulse inhibition of male, female, and TFM mice at prepulse decibels of 3, 8, 10, and 15. (Group means ± standard error of the mean (SEM)). (Note that as the prepulse gets louder, PPI increases for all groups, showing that as the prepulse increases animals are better able to use this information to predict the loud stimulus and inhibit their startle. TFMs consistently show a reduced PPI on this task, even for the loudest prepulse). Figure 2. Startle response of male, female, and TFM male mice to a 100 db acoustic pulse which is not preceded by a prepulse. Startle Response is shown in arbitrary units (Group means ± standard error of the mean (SEM)). TFM male mice showed a significantly reduced startle response compared to wild type males (p<.05). * These results suggest that the androgen receptor plays a role in the regulation of PPI and acoustic startle response in mice. Since TFM mice also have reduced circulating testosterone levels we cannot rule out the possibility that testosterone is acting on the estrogen receptor to increase PPI and startle response. Androgen receptor deficient (TFM) male mice display a very feminine pattern of prepulse inhibition TFM male mice also show a decreased startle response compared to wild type males Mice were genotyped using the polymerase chain reaction (PCR) technique to detect the TFM versus the wild type allele for the AR, and to detect the presence or absence of the Sry gene found only on the Y chromosome. At weaning the tip of the tail was clipped from each animal to obtain DNA for determining whether or not they were male, female, male TFM, or female TFM carriers. All animals except female TFM carriers were used in the proposed experiment. Wild type male (n=8), wild type female (n=13), and TFM male (n=13) mice were assessed for PPI at 4-6 months of age. PPI was measured in acoustic startle response chambers (San Diego Instruments). Animals were placed into the chamber for a duration of 18 minutes, the first 5 minutes of which is an acclimation period. For the remaining 13 minutes the fast muscle twitch startle responses of animals to a 100 decibel tone alone, or preceded by tones of 4, 8, 10, and 15 decibels were recorded via SR Lab software (San Diego Instruments). Each of these trials was repeated 5 times at pseudo-random intervals. After the test, animals were removed while the chamber was cleaned with 70% ethanol. Figure 2. Prepulse inhibition of male, female, and TFM mice averaged across all trials. (Group means ± standard error of the mean (SEM)). TFM’s show significantly reduced PPI compared to males (p<.001) and marginally reduced compared to females (p=.10). Males also showed significantly greater PPI than females (p<.05). TFM males also show the least overall PPI when averaged across all prepulse trials. Elements of the acoustic startle response (top) and prepulse inhibition to the acoustic startle response (bottom) 100 msec Pre Pulse Pulse 100 dB 40 msec