Deciphering the role of tau in hippocampal synaptic physiology

• Main Author: Regan, Philip
• Published: University of Bristol 2016
• Subjects: 616.8
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.685921

The microtubule stabilizing protein tau is enriched in axons of neuronal cells, where it plays important roles in axonal elongation and trafficking of intracellular cargo. Its propensity to aggregate and mislocalize to somatodendritic regions are considered central pathogenic effects in tauopathies such as Alzheimer's disease. However, it has recently become apparent that tau can also be located in dendritic post-synaptic structures under physiological conditions, although little is currently known about the role of tau under these circumstances. In this regard, this thesis has explored the role of tau protein in synaptic physiology. The effects of tau depletion upon synaptic plasticity processes were first examined in acute and organotypic hippocampal slices, revealing a selective deficit in NMOAR-dependent LTD. Subsequently, biochemical assays of tau phosphorylation coupled with electrophysiological characterization of neurons transfected with tau phosphorylation mutants revealed a specific requirement for tau phosphorylation at serine 396 in hippocampal LTD. Finally, electrophysiological analysis provided preliminary evidence for a larger extrasynaptic pool of AMPARs in tau-depleted neurons. These results are best explained by a model in which tau regulates the internalization or intracellular retention of AMPARs, and these effects are modified by the GSK-313 mediated phosphorylation of tau during LTD.