Reduced acoustic startle response and peripheral hearing loss in the5xFADmouse model of Alzheimer's disease

Abstract

Hearing dysfunction has been associated with Alzheimer's disease (AD) in humans, but there is little data on the auditory function of mouse models of AD. Furthermore, characterization of hearing ability in mouse models is needed to ensure that tests of cognition that use auditory stimuli are not confounded by hearing dysfunction. Therefore, we assessed acoustic startle response and pre-pulse inhibition in the double transgenic 5xFAD mouse model of AD from 3-4 to 16 months of age. The 5xFAD mice showed an age-related decline in acoustic startle as early as 3-4 months of age. We subsequently tested auditory brainstem response (ABR) thresholds at 4 and 13-14 months of age using tone bursts at frequencies of 2-32 kHz. The 5xFAD mice showed increased ABR thresholds for tone bursts between 8 and 32 kHz at 13-14 months of age. Finally, cochleae were extracted and basilar membranes were dissected to count hair cell loss across the cochlea. The 5xFAD mice showed significantly greater loss of both inner and outer hair cells at the apical and basal ends of the basilar membrane than wild-type mice at 15-16 months of age. These results indicate that the 5xFAD mouse model of AD shows age-related decreases in acoustic startle responses, which are at least partially due to age-related peripheral hearing loss. Therefore, we caution against the use of cognitive tests that rely on audition in 5xFAD mice over 3-4 months of age, without first confirming that performance is not confounded by hearing dysfunction.

Age‐related deterioration of motor function in male and female 5xFAD mice from 3 to 16 months of age

“…Together with previous research from our laboratory, this study provides a detailed characterization of the development of motor dysfunction in 5xFAD mice. As early as 3‐4 months of age 5xFAD mice have an age‐related reduction in acoustic startle response, which is at least partially due to motor dysfunction at older ages . At 9‐10 months of age, 5xFAD mice have reduced body weight, reduced rearing activity in the OF, impaired motor coordination on the rotarod, and impaired balance on the balance beam test.…”

“…There are many transgenic mouse models with mutant genes associated with AD, but only a subset of these models develops motor dysfunction . Motor dysfunction has been reported reliably in 5xFAD and APPSL/PS1KI mice . Impairments in motor function have been reported but are not always reliably detected in other mouse models, such as the Tg2576 and CRND8 mice .…”

“…A subset of these mice was then tested on the balance beam, wire suspension and grid suspension tests at 4, 7, 10, 13 and 16 months of age (Table S3). These mice were then tested on the acoustic startle and prepulse inhibition, and the results have been published elsewhere, and used here only for correlational analyses. Mice were handled only during weekly cage changes prior to the experiment, and were acclimated briefly (5‐10 minutes) to the testing rooms prior to each behavioral test.…”

Whisker exploration behaviours in the 5xFAD mouse are affected by sex and retinal degeneration

“…13 Behaviourally, the 5xFAD mice have memory impairments, showed by a lack of recognition for novel objects at 6 to 7 months of age 14 and spatial memory deficits. 15,16 They also have motor impairments after 9 months of age, [17][18][19] age-related deafness 20 and social impairments 11 from 12 months of age. The 5xFAD mice also show a reduction of inhibitory interneurons in Layer IV of the whisker barrel cortex, which leads to changes in vibrissae-related behaviour that include a lack of whisker barbering in the home cage and an avoidance of enclosed spaces, which dissipates when the whiskers are trimmed.…”

Acoustic startle modification as a tool for evaluating auditory function of the mouse: Progress, pitfalls, and potential

“…Commonly used to screen for sensorimotor gating deficits and drug effects in models of neuropsychological disorders (Swerdlow et al 2001, 2016; Geyer et al 2002) and to evaluate the effects of genes on sensorimotor behavior (Plappert and Pilz 2001), ASR modification procedures have gained popularity as behavioral measures of hearing function in rodents due to their perceived ease of implementation. For instance, studies have identified temporal, spatial, and hearing in noise processing deficits in mutant strains (Lauer and May 2011; Jalabi et al 2014; Truong et al 2014; Altschuler et al 2015; Karcz et al 2015; Tziridis et al 2016; Ison et al 2017), abnormal responsivity after chronic or acute noise exposure (Lauer and May 2011; Hickox and Liberman 2014; Salloum et al 2014; Longenecker et al 2016), abnormal reactivity to sounds in mouse models of early-onset hereditary hearing loss, fragile X syndrome, and Alzheimer’s disease (Chen and Toth 2001; McGuire et al 2015; O’Leary et al 2017), auditory processing deficits in mild traumatic brain injury (Amanipour et al 2016), and hormonal effects on auditory processing (Charitidi et al 2012). Other studies have used ASR modification procedures as behavioral readouts during physiological manipulationand development of neurons in the auditory pathway (Weible et al 2014a, b; Aizenberg et al 2015; Moyer et al 2015).…”