Increased neuronal activity in motor cortex reveals prominent calcium dyshomeostasis in tauopathy mice.

Perturbed neuronal Ca homeostasis is implicated in Alzheimer's disease, which has primarily been demonstrated in mice with amyloid-β deposits but to a lesser and more variable extent in tauopathy models. In this study, we injected AAV to express Ca indicator in layer II/III motor cortex neurons and measured neuronal Ca activity by two photon imaging in awake transgenic JNPL3 tauopathy and wild-type mice. Various biochemical measurements were conducted in postmortem mouse brains for mechanistic insight and a group of animals received two intravenous injections of a tau monoclonal antibody spaced by four days to test whether the Ca dyshomeostasis was related to pathological tau protein. Under running conditions, we found abnormal neuronal Ca activity in tauopathy mice compared to age-matched wild-type mice with higher frequency of Ca transients, lower amplitude of peak Ca transients and lower total Ca activity in layer II/III motor cortex neurons. While at resting conditions, only Ca frequency was increased. Brain levels of soluble pathological tau correlated better than insoluble tau levels with the degree of Ca dysfunction in tauopathy mice. Furthermore, tau monoclonal antibody 4E6 partially rescued Ca activity abnormalities in tauopathy mice after two intravenous injections and decreased soluble pathological tau protein within the brain. This correlation and antibody effects strongly suggest that the neuronal Ca dyshomeostasis is causally linked to pathological tau protein. These findings also reveal more pronounced neuronal Ca dysregulation in tauopathy mice than previously reported by two-photon imaging that can be partially corrected with an acute tau antibody treatment.