The Impact of Tauopathy on Ultrasonic Vocalization in a Mouse Model of Frontotemporal Dementia

Abstract

Tauopathy features in many neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP‐17), where aggregation of misfolded and hyperphosphorylated tau impairs cytoplasmic function and axonal transport, and ultimately leads to cell death. Common complications in patients with FTDP‐17 include upper airway dysfunctions such as swallowing and voice disorders and mutism, and in previous work we demonstrated that upper airway and swallowing complications also occur in a mouse model of FTDP‐17 carrying the P301L mutation. Because of these complications, we investigated: 1) Whether Tau‐P301L transgenic mice also have impaired vocalization, owing to vocalization requiring expiratory airflow through the larynx; and 2) The underlying pathology in Tau‐P301L mice linking irregular vocal patterns to tauopathy.Male Tau‐P301L mice on an FVB/N background interacted with a female wildtype (WT) mouse in estrous for 5 minutes, during which ultrasonic vocalizations (USV) were recorded (UltraSoundGate condensor microphone, Avisoft Berlin, Germany). USV recordings were obtained from Tau‐P301L and wild‐type mice aged 3, 5, 7 and 9 months. In parallel, social interactivity was also monitored. While a trend for a lower number and duration of USV and a higher frequency of USV was observed in Tau‐P301L mice, USV in both Tau‐P301L and WT mice were diverse, with the large variance in the number, duration and frequency of vocalizations in Tau‐P301L and WT mice indicating no statistical difference between groups. However, in each age group, the number and duration of USV in a subpopulation of Tau‐P301L mice was lower than and outside the range of WT mice. In these Tau‐P301L mice, 80% of calls were less than 45 msec duration (vs 55% in WT), while 20% of calls were greater than 45 msec duration (vs 45% in WT). The same subpopulation of Tau‐P301L mice displayed a decreased complexity (frequency modulation) and repertoire (call types) of USV compared to WT. These changes to USV in a subpopulation of Tau‐P301L mice were already present in mice aged 3 months, and the parameters measured deteriorated with age. Immunohistochemical analysis identified presence of anti‐human PHF‐Tau (clone AT8, ThermoScientific) and anti‐tau phosphoserine 199/202 (Millipore) immunoreactivity in cell bodies of upper airway and vocalization‐related brain nuclei, including the Periaqueductal Gray (PAG), Nucleus Ambiguus and Kölliker Fuse (KF) nuclei. Further, compared to WT, 40% fewer forkhead box protein P2 (FOXP2) immunoreactive cell bodies were present in the KF of 9‐month‐old Tau‐P301L mice, while the number of FOXP2 immunoreactive cells in the PAG was similar.Our data indicate: 1) an early onset of vocalization disorder in a subpopulation of Tau‐P301L mice; 2) a deterioration in USV that progresses as Tau‐P301L mice age; and 3) presence of tauopathy and neurodegeneration in brain regions that regulate the upper airways and vocalization. Our results also provide a base for examining whether vocalization/voice disturbances are a potential ‘early’ detection diagnostic for dementia.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.