Synaptic dysfunction caused by truncated tau is associated with hyperpolarization-activated cyclic nucleotide-gated channelopathy

Abstract

Neurodegenerative tauopathies are characterized by deposition in the brain of highly phosphorylated and truncated forms of tau, but how these impact on cellular processes remains unknown. Here, we show that hyperpolarization-induced membrane voltage ‘sag’, which is dependent on hyperpolarization-activated inward-rectifying (Ih) current and hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels, is increased in the Tau35 mouse model of human tauopathy. Expression of Tau35, corresponding to a fragment comprising the carboxy-terminal half of tau first identified in human tauopathy brain, reduces dendritic branching in mouse brain and in cultured hippocampal neurons, and decreases synaptic density. Neuronal expression of Tau35 results in increased tau phosphorylation and significant disruption to synaptic ultrastructure, including marked and progressive reductions in synaptic vesicle counts and vesicle cluster density. Ultrastructural analysis reveals that the positioning of synaptic vesicles is perturbed by Tau35, causing vesicles to accumulate at sites adjacent to the active zone and at the lateral edges of the cluster. These structural changes induced by Tau35 correlate with functional abnormalities in network activity, including increased width, reduced frequency and slower rate of rise of spontaneous excitatory postsynaptic currents. Collectively, these changes are consistent with a model in which disease-associated tau species disrupt network connectivity and signaling. Our results suggest that the persistence of truncated tau in the brain may underpin the catastrophic synaptic dysfunction observed during the development and progression of human tauopathy.