Research reportTauopathy in the periaqueductal gray, kölliker-fuse nucleus and nucleus retroambiguus is not predicted by ultrasonic vocalization in tau-P301L mice
Introduction
Tauopathy is a common hallmark of many neurodegenerative diseases, including Alzheimer’s disease, corticobasal degeneration and frontotemporal dementia (FTD) with Parkinsonism [[1], [2], [3], [4], [5]]. It is characterized by the aggregation of misfolded and hyperphosphorylated tau protein in the cytoplasm of neurons, which results in aberrant interaction of tau protein with microtubules, impairment of axonal transport and changes in the morphological and functional integrity of neuronal synapses and somas [2,6].
Frontotemporal dementia and Parkinsonism linked to Chromosome 17 (FTDP-17) commonly arises from mutations in the microtubule-associated protein tau gene. Of the 53 currently known pathogenic mutations linked to FTDP-17, one of the most common is the P301L mutation [7]. In humans, this mutation is associated with cognitive decline [8] and non-cognitive symptoms, such as behavioural and motor disturbances [5].
Besides these neurological impairments, speech disorders are common symptoms in FTDP-17 patients [[9], [10], [11]]. FTDP-17-related speech disorders often manifest early in tauopathy and progress to mutism [12]. Thus, brainstem laryngeal motor control pathways may undergo tauopathy and neurodegeneration. Although brainstem tauopathy is receiving increasing recognition in postmortem studies [[13], [14], [15], [16]], how brainstem tauopathy contributes to the development and progression of speech disorders in FTDP-17 and other tauopathy-related disorders is not well understood.
Here, we have studied whether the emergence and progression of irregular ultrasonic vocalization (USV) in transgenic tau-P301L mice carrying the P301L mutation [17] is predictive of the presence of tauopathy in brainstem vocalization centres. Tau-P301L mice develop respiratory dysfunction primarily associated with paradoxical vocal cord movement in the larynx (i.e. constriction of vocal fold during inspiration) [18,19] at around 9 months of age, during the terminal phase of disease progression [20,21]. Considering that the production of ultrasonic vocalization (USV) in rodents requires laryngeal airflow modulation via laryngeal adductors [[22], [23], [24], [25]], reports that tau-P301L mice become mute at the terminal stage of disease progression [26] are not surprising.
Irregular USV production and mutism in tau-P301L mice has been correlated with tauopathy in the periaqueductal gray (PAG), Kölliker-Fuse nuclei (KF) and nucleus retroambiguus (NRA) [26], regions of the midbrain and brainstem that have been designated as vocalization centres in mammals [[27], [28], [29], [30], [31], [32], [33], [34], [35], [36]]. Importantly, contrary to other mouse models of tauopathy incorporating the P301L mutation (e.g. the rTg(tauP301L)4510 mouse model [37]), tau-P301L mice develop tauopathy predominantly in the midbrain, brainstem and spinal cord [17,20,21,26,38]. Thus, it was concluded that mutism in tau-P301L mice is closely associated to non-cognitive dysfunction of the laryngeal control circuit [26].
The present study aimed to identify whether deficits in USV production are an early predictor for disease onset that could serve as an indicator of tauopathy-related phenotype progression, and a potential pre-clinical diagnostic for frontotemporal dementia [39]. We investigated whether USV deficits in male tau-P301L mice were associated with tauopathy in the PAG, KF and NRA using a previously described experimental model of social male-female interaction [[40], [41], [42], [43], [44], [45], [46], [47], [48], [49]]. USV production in tau-P301L mice was examined at the following three age periods: 1) 3–4 months, during which tau-P301L mice are asymptomatic, with no deficits or tauopathy reported at this age [17,20,50]; 2) 5–6 months, a period prior to symptom onset in tau-P301L mice that include respiratory-related deficits and the emergence of tauopathy from 7 months of age, but no apparent irregular locomotor activity [17,20]; and 3) 8–9 months, a symptomatic stage in which the majority of tau-P301L suffer motor-related behavioural disturbances and present with tauopathy [17,20,51].
Section snippets
Animals
USVs were examined using 25 male wildtype FVB/N mice and 56 male transgenic tau-P301L mice expressing the longest human tau isoform with the P301L mutation (tau-4R/2N-P301L) under control of the mouse thy1 gene promoter [17]. A further 40 female wildtype FVB/N mice were used during social male-female interaction with male FVB/N wildtype or tau-P301L mice. Animals from the same strain were group housed (4–5 mice per cage) and separated by gender and age prior to testing, and singly housed 1 h
USV is similar in tau-P301L and wildtype FVB/N mice
Overall, mice from both genotypes emitted similar USV patterns during social male-female interaction at all age-groups (Fig. 1). Even symptomatic tau-P301L mice that developed end-stage motor dysfunction (Fig. 1B; n = 5) emitted USV patterns similar to wildtype mice (Fig. 1A) and asymptomatic/pre-symptomatic tau-P301L mice.
Further analysis of USV parameters included an examination of the: 1) number of USVs per min (Fig. 2A); 2) mean duration of each individual USV (millisecs, Fig. 2B); 3) total
Discussion
The present study investigated USV in male tau-P301L mice, a mouse model of tauopathy in human frontotemporal dementia [17]. We examined USV at the following 3 stages of disease progression, based on the progressive motor impairment that occurs in tau-P301L mice over time: tau-P301L mice aged 3–4 months, when animals are asymptomatic [17,20]; 5–6 months, a pre-symptom onset period prior to the emergence of tauopathy and motor deficits [17]; and 8–9 months, a symptomatic stage when motor-related
Conclusion
Contrary to a previous study, our present experiments did not reveal a significant USV disorder in male tau-P301L mice during an experimental protocol of male-female interaction, even at late stages of progressing tauopathy (8–9 months of age). The different outcome compared to the previous study might originate in the stronger stimulus for male USV, which were triggered in our study by the presence of female mice in oestrous. The fact that tauopathy in the midbrain PAG, pontine KF and
Conflict of interest statement
The authors have no conflicts of interest to declare.
Funding
This work was supported by the: National Health and Medical Research Council of Australia (NHMRC) [Project Grant APP1165529] to MD and DS; NHMRC-ARC dementia development research fellowship [APP1111552] to ELB; Melbourne Research Scholarship (University of Melbourne) [181858] to PT-B.
Acknowledgements
We thank Dr. Clare Parish and Dr. Lachlan Thompson (Discovery Neuroscience theme, Florey) for generous use of freezing microtome and microscopy facilities.
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