Neurological Disorders: Prepulse Inhibition
Prepulse inhibition is a pre-attentive process that has been shown to be deficient in patients with schizophrenia. This reduced ability to filter out environmental stimuli may contribute to both positive and negative symptoms of the disease. This test has been successfully used to detect phenotypes in knockout mice. For example, impaired prepulse inhibition of startle response has been observed in DAT (dopamine transporter) KO mice (Ralph et al., 2001). Anti-psychotics can ameliorate some deficits in prepulse inhibition, therefore genetic inhibition of a target that can increase prepulse inhibition may presage a small-molecule therapeutic that can help patients with their disorder. The prepulse inhibition of the startle response assay is an automated measure of the startle response both with and without various intensities of prepulses. Targets whose genetic inhibition produces changes in prepulse inhibition without changes in the startle response itself may be excellent for the discovery of new therapeutics. This test employs a San Diego Instruments SR-Lab startle response system. Prepulse inhibition of the acoustic startle reflex occurs when a loud 120 decibel (dB) startle-inducing tone is preceded by a softer (prepulse) tone. The prepulse inhibition paradigm consists of six different trial types (70 dB background noise, 120 dB alone, 74+120 dB at postpartum day 4, 78+120 dB at postpartum day 8, 82+120 dB at postpartum day 12, and 90+120 dB at postpartum day 20) each repeated in pseudorandom order six times for a total of 36 trials. The maximum response to the stimulus (Vmax) is averaged for each trial type. The percentage inhibition of the animal's response to the startle stimulus is calculated for each prepulse intensity and then graphed. This test is being used increasingly as a model of human schizophrenia and a test for antipsychotic drugs.
Displayed below is a sample graph of how prepulse inhibition observations are presented. In comprehensive phenotypic data packages graphs are interactive. Raw or calculated data and statistics can be seen by clicking on points in the graph.
Figure illustrates percentage of prepulse inhibition for male and female mutant mice. Percent prepulse inhibition for wild type littermates (green circle), heterozygous (blue triangle). and homozygous (red diamond) mice are plotted against long-term historical inhibition percentages (+/- 2 standard deviations) for wild type animals (green shading). Long-term historical values are derived from data collected on more than 10,000 wild type mice.
Ralph R, Paulus M, Fumagalli F, Caron M, Geyer MA. (2001) Prepulse inhibition deficits and perseverative motor patterns in dopamine transporter knockout mice: Differential effects of D1 and D2 receptor antagonists
, The Journal of Neuroscience, 21(1):305-313