5XFAD mice show early-onset gap encoding deficits in the auditory cortex

Abstract

Early detection will be crucial for effective treatment or prevention of Alzheimer's disease. The identification and validation of early, non-invasive biomarkers is therefore key to avoiding the most devastating aspects of Alzheimer's. Measures of central auditory processing such as gap detection have recently emerged as potential biomarkers in both human patients and the 5XFAD mouse model of Alzheimer's. Full validation of gap detection deficits as a biomarker will require detailed understanding of the underlying neuropathology, including which brain structures are involved and how the operation of neural circuits is affected. Here we show that 5XFAD mice exhibit gap detection deficits as early as 2 months of age, well before development of Alzheimer's-associated pathology. We then examined responses of neurons in auditory cortex to gaps in white noise. Both gap responses and baseline firing rates were robustly and progressively degraded in 5XFAD mice compared to littermate controls. These impairments were first evident at 2-4 months of age in males, and 4-6 months in females. This demonstrates early-onset impairments to the central auditory system, which could be due to damage in auditory cortex, upstream subcortical structures, or both.

Early functional and cognitive declines measured by auditory evoked cortical potentials in Alzheimer’s disease mice

“…The significant reduction was found in ABR peaks IV and V, which are generated by neural activities of inferior colliculus, nuclei of lateral lemniscus, and medial geniculate body in the upper brainstem. It was also reported that the 5xFAD mice have early onset of deficits in auditory gap detection at 2 months old (Kaylegian et al, 2019;Weible et al, 2020). These data demonstrated that dysfunctions of hearing could occur much earlier than the typical AD phenotypes occurring.…”

“…The significant reduction of ABR peaks IV and V (which are generated by neural activities of inferior colliculus, nuclei of lateral lemniscus, and medial geniculate body in the upper brainstem) in the APP/PS1 AD mice could be found at 3 months old (Liu et al, 2020). It was also reported that the 5xFAD mice have early onset of deficits in auditory gap detection, which could be detectable at about 2 months old and became progressive worse afterwards (Kaylegian et al, 2019; Weible et al, 2020). These data demonstrated that dysfunctions of hearing occurred much earlier than the appearance of typical AD phenotypes, such as spatial learning deficit, in APP/PS1 AD mice by 6-7 months of age (Reiserer et al, 2007; Ordonez-Gutierrez et al, 2015, 2016).…”

“…We previously reported that hearing loss measured as ABR threshold occurred in APP/PS1 AD mice as early as 2-3 months old (Liu et al, 2020). 5×FAD mice also had early onset of deficits in auditory gap detection at 2 months old (Kaylegian et al, 2019; Weible et al, 2020). It was reported that auditory sensory and cognitive cortical potentials in AD persons could be abnormal approximately 10 years before AD becomes apparent (Golob et al, 2009).…”

“…Our previous study demonstrated that auditory brainstem response (ABR), which reflects the function and integrity of the auditory pathway in the brainstem, had apparent reduction in APP/PS1 AD mice at the age of 3 months old (Liu et al, 2020), prior to occurrence of spatial learning deficit in this AD mouse model by age of 6-7 months old (Reiserer et al, 2007;Ordonez-Gutierrez et al, 2015, 2016. Recent studies also demonstrated that 5xFAD mice have early onset of deficits in auditory gap detection (Kaylegian et al, 2019;Weible et al, 2020). These studies suggest that AD could cause hearing function decline at the early stage, and that hearing function tests could provide important information for detecting AD at the early stage.…”

“…Recent studies also demonstrated that AD could cause auditory functional changes. It has been reported that the 5xFAD mice have early onset of deficits in auditory gap detection (Kaylegian et al, 2019; Weible et al, 2020). These studies suggest that AD could cause hearing function decline at the early stage.…”