Increased auditory startle response and reduced prepulse inhibition of startle in transgenic mice expressing a double mutant form of amyloid precursor protein.
Prepulse inhibition (PPI), a form of sensorimotor gating, occurs when an auditory startle response is markedly inhibited by a preceding sub-threshold stimulus (prepulse). Deficits in PPI have been demonstrated in patients with certain psychiatric disorders, such as schizophrenia, and in laboratory animals following specific pharmacological manipulations. Patients with Alzheimer's disease (AD) have not been tested in PPI, but have been shown to have abnormal sensory gating in another paradigm. Transgenic (Tg) CRND8 mice, which model Alzheimer's disease, carry the Swedish and Indiana familial Alzheimer's disease mutations of the human amyloid precursor protein gene and show age-related increases in beta-amyloid (Abeta) production, as well as plaque deposition. The present experiment investigated auditory startle threshold and PPI in TgCRND8 mice at various ages. In two longitudinal studies, PPI was examined in male TgCRND8 mice and non-transgenic (non-Tg) controls at 6-8 weeks of age (pre-plaque), and every 2 weeks thereafter until all mice were at least 16 weeks old (post-plaque). In a cross-sectional study, three different age sets of nai;ve TgCRND8 and non-Tg mice were tested: 10-12, 12-14, and 15-17 weeks old. In all three studies, TgCRND8 mice consistently and robustly demonstrated an enhanced response to a range of auditory startle stimuli compared to non-Tg mice. In addition, the TgCRND8 mice exhibited modest reductions in PPI, compared to non-Tg controls. These PPI deficits were present at pre- and post-plaque time points and did not appear to intensify with age; thus, they do not seem to correlate with the known neuropathology of TgCRND8 mice.
McCool
Martha F
MF
CNS Biological Research, Schering-Plough Research Institute, K15-2-2600, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Varty
Geoffrey B
GB
Del Vecchio
Robert A
RA
Kazdoba
Tatiana M
TM
Parker
Eric M
EM
Hunter
John C
JC
Hyde
Lynn A
LA
D000161:Acoustic Stimulation / Q000379:methods*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics*; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009433:Neural Inhibition / Q000235:genetics; D013216:Reflex, Startle / Q000235:genetics*
D016564:Amyloid beta-Protein Precursor