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

Perturbed neuronal Ca²⁺ 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 Ca²⁺ indicator in layer II/III motor cortex neurons and measured neuronal Ca²⁺ 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 Ca²⁺ dyshomeostasis was related to pathological tau protein. Under running conditions, we found abnormal neuronal Ca²⁺ activity in tauopathy mice compared to age-matched wild-type mice with higher frequency of Ca²⁺ transients, lower amplitude of peak Ca²⁺ transients and lower total Ca²⁺ activity in layer II/III motor cortex neurons. While at resting conditions, only Ca²⁺ frequency was increased. Brain levels of soluble pathological tau correlated better than insoluble tau levels with the degree of Ca²⁺ dysfunction in tauopathy mice. Furthermore, tau monoclonal antibody 4E6 partially rescued Ca²⁺ 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 Ca²⁺ dyshomeostasis is causally linked to pathological tau protein. These findings also reveal more pronounced neuronal Ca²⁺ dysregulation in tauopathy mice than previously reported by two-photon imaging that can be partially corrected with an acute tau antibody treatment.