Abstract
Tau is a highly soluble microtubule-associated protein that acts within neurons to modify microtubule stability. However, abnormally phosphorylated tau dissociates from microtubules to form oligomers and fibrils which associate in the soma-dendritic compartment. Although tau can form neurofibrillary tangles (NFTs), it is the soluble oligomers that appear to be the toxic species. There is, however, relatively little quantitative information on the concentration- and time-dependent actions of soluble tau oligomers (oTau) on the electrophysiological and synaptic properties of neurons. Here, whole-cell patch clamp recording was used to introduce known concentrations of oligomeric full-length tau-441 into mouse hippocampal CA1 pyramidal and neocortical layer-V thick-tufted pyramidal cells. oTau increased input resistance, reduced action potential amplitude and slowed action potential rise and decay kinetics. oTau injected into presynaptic neurons induced the run-down of unitary EPSPs which was associated with increased short-term depression. In contrast, introduction of oTau into postsynaptic neurons had no effect on basal synaptic transmission, but markedly impaired the induction of long-term potentiation. Consistent with its effects on synaptic transmission and plasticity, oTau puncta could be observed in the soma, axon and in the distal dendrites of injected neurons.
Significance statement The protein tau is highly expressed in neurons and is involved in maintaining neuronal structure. In diseases such as Alzheimer’s disease, tau can form oligomers, which consist of tau molecules joined together. There is growing evidence that these tau oligomers are toxic to neurons, although their precise actions are still being characterised. We have taken the approach of introducing structurally-defined tau-441 oligomers into neurons via the recording electrode (a method previously published by Kaufmann et al 2016). This method allowed us to provide detailed characterisation of the concentration- and time- dependent actions of tau oligomers on neuronal properties. We have found that tau interferes with the action potential waveform, modifies synaptic transmission and can block events that probably underlie memory storage.
Footnotes
The authors declare no competing interests.
EH holds a BBSRC funded doctoral fellowship. Part of this work was funded by the Alzheimer’s Research Trust.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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