Motor Deficits in a Mouse Model of Frontotemporal Dementia: Cortical Tau Pathology and Reduced Nigrostriatal Dopaminergic Markers

Mice carrying tauopathy-associated mutations are considered good models for frontotemporal dementia because they replicate key features of the human disease. In carriers of the P301S tau mutation, these include degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), reduced striatal dopamine levels, and motor deficits. Such parkinsonian symptoms have been reproduced in mouse models and are accompanied by weakened glutamatergic transmission from the motor and premotor cortex to the striatum. Here, we examined transgenic female homozygous (L66-Homo) and female heterozygous (L66-Het) Line 66 mice, which express the full-length human tau protein carrying the P301S and G335D mutations and NMRI mice as controls. Our focus was on the movement anomalies recorded using the RotaRod and Traction tests, together with histological markers of tauopathy, dopaminergic and glutamatergic systems and possible neurological markers in the motor cortex, striatum and SNpc. Compared to wild-type controls, 9-month-old L66-Homo mice presented with distinct motor impairments in both tests, which were not seen in aged matched L66-Het mice. Compared to L66-Het mice, L66-Homo mice exhibited: (1) more pronounced impairment of the dopaminergic phenotype in SNpc neurons; (2) exacerbated loss of tyrosine hydroxylase staining in striatum; (3) weaker vesicular monoamine transporter 2 staining in SNpc, striatum and frontal cortex; (4) stronger anti-tau staining in striatum and frontal cortex; (5) similar degree of degeneration in frontal cortex; and (6) similar decline in glutaminase staining in striatum and frontal cortex. Surprisingly, no tau-enriched labelling was present in SNpc in both L66-Homo and L66-Het. Therefore, motor impairments in female L66-Homo mice are associated with tau pathology in the striatum and motor cortex, together with a loss of the dopaminergic markers in the SNpc despite an absence of detectable tau immunoreactivity. Altered functional interactions between the striatum and SNpc may contribute to the observed dopamine loss and motor impairment in this mouse model. As only female mice were studied, the applicability of these findings to males remains to be established.