Early behavioural markers of disease in P301S tau transgenic mice

Abstract

The present study aimed at characterizing the early behavioural changes preceding the onset of disease in a transgenic mouse model of tauopathy. Mice transgenic for human P301S tau protein exhibit many characteristics of human tauopathies, including neurodegeneration, the formation of neuronal tau inclusions in the brain and the development of a pronounced motor phenotype by 5 months of age. In this study we analyzed the ultrasonic vocalization pattern in the first week of life and the response to nest-related olfactory stimuli on postnatal day 10 in both homozygous and heterozygous transgenic mice in comparison with the behavioural responses of C57BL/6J pups. Expression of human tau in the brain and spinal cord was evaluated by Western blot analysis. Homozygous P301S tau transgenic and C57BL/6J mice were also assessed for motor coordination in the Rotarod apparatus at 1, 2, 3 and 4 months of age, and spatial learning and spontaneous behaviour were evaluated at 2 months in the Morris water-maze and the open-field test. Results showed that P301S pups emitted more ultrasounds than C57BL/6J pups when separated from the mother. Two-month-old P301S mice displayed a hyperactive profile, as shown by increased swimming speed, enhanced locomotion and exploration of a novel object in the open field. However, the spatial task acquisition was unaltered. Decline of motor coordination capacities was evident only by the third month of age in the rotarod test. Behavioural abnormalities can be detected well before occurrence of neurodegeneration in this transgenic strain, thus representing precocious markers of pathology.