Neuronal hypofunction and network dysfunction in a mouse model at an early stage of tauopathy

Abstract

Introduction: It is unclear how early neuronal deficits occur in tauopathies, if these are associated with changes in neuronal network activity, and if they can be alleviated with therapies.

Methods: To address this, we performed in vivo two-photon Ca²⁺ imaging in tauopathy mice at 6 versus 12 months, compared to controls, and treated the younger animals with a tau antibody.

Results: Neuronal function was impaired at 6 months but did not deteriorate further at 12 months, presumably because cortical tau burden was comparable at these ages. At 6 months, neurons were mostly hypoactive, with enhanced neuronal synchrony, and had dysregulated responses to stimulus. Ex vivo, electrophysiology revealed altered synaptic transmission and enhanced excitability of motor cortical neurons, which likely explains the altered network activity. Acute tau antibody treatment reduced pathological tau and gliosis and partially restored neuronal function.

Discussion: Tauopathies are associated with early neuronal deficits that can be attenuated with tau antibody therapy.

Highlights: Neuronal hypofunction in awake and behaving mice in early stages of tauopathy. Altered network activity disrupted local circuitry engagement in tauopathy mice. Enhanced neuronal excitability and altered synaptic transmission in tauopathy mice. Tau antibody acutely reduced soluble phospho-tau and improved neuronal function.

Keywords: calcium imaging; immunotherapy; mouse model; network dysfunction; neuronal hypofunction; tau protein; tauopathy; two‐photon imaging.