BDNF-mediated synaptic facilitation in the hippocampus is impaired in the Thy-Tau22 transgenic tau model

Abstract

Tau pathology is encountered in more than 20 neurodegenerative disorders including Alzheimer's disease (AD) and fronto-temporal dementia. It results from the aggregation of hyperphosphorylated tau proteins into filaments. Tau pathology is correlated to cognitive deficits in AD patients. Interestingly, in most transgenic tau models, Tau pathology leads to cognitive impairments and changes and synaptic alterations before any neuronal death. Brain-derived neurotrophic factor (BDNF)/TrkB signalling is a key actor in hippocampal synaptic plasticity and memory. BDNF/TrkB signalling was evaluated in the Thy-Tau22 transgenic mice by biochemical, electrophysiological and immunohistochemical approaches. Thy-Tau22 overexpresses a human mutated Tau isoform and exhibits progressive development of hippocampus AD-like Tau pathology together with memory impairments, in absence of neuronal loss from 3 to 12 months old. First, in this model, there is no major loss of BDNF/TrkB expression with the development of the hippocampal Tau pathology. Second, there is no evidence of any change in expression of proteins involved in the classical BDNF/TrkB signalling pathway between Thy-tau22 and littermate controls. However, BDNF-mediated synaptic facilitation, as visualized in wild-type mice, by increasing the slope of field excitatory post-synaptic potentials (fEPSPs) in the stratum radiatum of the CA1 region, is never observed in Thy-Tau22 mice. This lack of responsiveness is observed as early as 4 months old while TrkB receptor remains activable and forskolin-induced facilitation is not affected in Thy-tau22 mice. In our slice electrophysiology experiments, BDNF-mediated synaptic facilitation is dependent of NMDA receptors. In fact, in wild-type mice, ifenprodil, a selective NR2B antagonist, abolishes BDNF-induced synaptic potentiation of fEPSP. Interestingly, in Thy-tau22 mice, protein levels of NMDA receptor subunits are reduced compared to littermate controls whereas levels of AMPA receptors remain unchanged. In line, depression of the fEPSP slope induced by a direct NMDA application on wild-type slices is significantly reduced in Thy-Tau22 mice while no difference between genotypes can be observed following NBQX application, an AMPA receptor antagonist. Altogether, our data support that, even with a functional BDNF/TrkB canonical transduction signalling, Tau pathology induces alteration of NMDA-dependent synaptic response to BDNF, possibly contributing to memory alterations.