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252 Prepulse Inhibition is Reduced in Mice with the Testicular Feminization Mutation
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 48824
•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.
Methods
•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.
Androgen receptor deficient (TFM) male mice
display a very feminine pattern of prepulse inhibition
TFM males also show the least overall PPI when
averaged across all prepulse trials.
Average PPI
Prepulse Inhibition
80%
70%
70%
60%
60%
50%
Male
40%
30%
Female
Average %PPI
• 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.
Summary
tfm
20%
10%
PP3
PP8
PP10
PP15
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).
50%
Male
40%
Female
30%
TFM
20%
0%
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).
Startle Response
70
60
50
Male
40
Female
30
TFM
20
•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.
Significance
TFM male mice also show a decreased startle
response compared to wild type males
80
• 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.
10%
0%
Startle Response (Arbitrary Units)
• 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.
Results
%PPI
Introduction
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.
10
0
Elements of the acoustic startle response (top) and prepulse
inhibition to the acoustic startle response (bottom)
100 dB 40 msec
Pulse
*
100 msec
Pre Pulse
Pulse
Acknowledgments
Supported by The MSU Foundation and NIH
NS045195 & MH58703