Microtubule-associated protein tau is essential for long-term depression in the hippocampus

Tetsuya Kimura 0 1 Daniel J. Whitcomb 0 1 Jihoon Jo 0 1 Philip Regan 0 1 Thomas Piers 0 1 Seonghoo Heo 0 1 Christopher Brown 0 1 Tsutomu Hashikawa 0 1 Miyuki Murayama 0 1 Heon Seok 0 1 Ioannis Sotiropoulos 0 1 Eunjoon Kim 0 1 Graham L. Collingridge 0 1 Akihiko Takashima 0 1 Kwangwook Cho 0 1 0 Tetsuya Kimura, Daniel J. Whitcomb , Jihoon Jo, Philip Regan, Thomas Piers, Seonghoo Heo, Christopher Brown, Tsutomu Hashikawa, Miyuki Murayama, Heon Seok, Ioannis Sotiropoulos, Eunjoon Kim, Graham L. Collingridge, Akihiko Takashima and Kwangwook Cho Phil. Trans. R. Soc. B 2014 369, 20130144, published 2 December 2013 1 Acknowledgements. We thank Drs P. St. George-Hyslop (University of Cambridge), Eckhard Mandelkow (German Center for Neurodegenera- tive Disease), M. Vitek (Duke University), O. Almeida (Max Planck Institute of Psychiatry), N. Sausa (University of Minho) and Hana Dawson (Duke University) for critical discussion Articles on similar topics can be found in the following collections neuroscience (542 articles) physiology (78 articles) Receive free email alerts when new articles cite this article - sign up in the box at the top right-hand corner of the article or click here References Subject collections Email alerting service rstb.royalsocietypublishing.org Research Cite this article: Kimura T et al. 2014 Microtubule-associated protein tau is essential for long-term depression in the hippocampus. Phil. Trans. R. Soc. B 369: 20130144. http://dx.doi.org/10.1098/rstb.2013.0144 One contribution of 35 to a Discussion Meeting Issue Synaptic plasticity in health and disease. Subject Areas: neuroscience, physiology These authors contributed equally to this Microtubule-associated protein tau is essential for long-term depression in the hippocampus The microtubule-associated protein tau is a principal component of neurofibrillary tangles, and has been identified as a key molecule in Alzheimers disease and other tauopathies. However, it is unknown how a protein that is primarily located in axons is involved in a disease that is believed to have a synaptic origin. To investigate a possible synaptic function of tau, we studied synaptic plasticity in the hippocampus and found a selective deficit in long-term depression (LTD) in tau knockout mice in vivo and in vitro, an effect that was replicated by RNAi knockdown of tau in vitro. We found that the induction of LTD is associated with the glycogen synthase kinase-3-mediated phosphorylation of tau. These observations demonstrate that tau has a critical physiological function in LTD. 1. Introduction The microtubule-associated protein tau (MAPT) gene is located on chromosome 17 and consists of 16 exons [1]. Alternative splicing leads to six isoforms of tau, all of which contain an amino-terminal projection domain and carboxy-terminal with microtubule-binding repeats [2]. Tau contains several critical serine and threonine residues, the phosphorylation of which regulates its binding affinity for microtubules [3,4]. It is believed that through this binding, tau has major roles in stabilizing microtubules [5]. During neuronal development, tau expression is increased in response to nerve growth factor [6], and subsequently enriched in axons, a process that is required for maintaining axon morphology [7]. The extent to which tau may have additional functions unrelated to axonal microtubule stabilization, however, is not known. & 2013 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0/, which permits unrestricted use, provided the original author and source are credited. Tauopathies, such as Alzheimers disease (AD), are characterized by widespread accumulation of hyperphosphorylated tau. Once hyperphosphorylated, tau is known to accumulate in somatodendritic compartments and forms the core component of neurofibrillary tangles (NFTs) [8]. It is generally believed that hyperphosphorylation of tau is the critical step in causing it to be missorted from the axon to dendrites, where it interferes with neuronal function [9]. Associated with this accumulation, there is a loss of synapses and eventually neurons [10,11]. However, the mechanism by which this occurs is unknown. Increasing evidence suggests that in AD, synaptic dysfunction may initiate the cascades that result in cognitive impairment and neurodegeneration. For example, it is well established that oligomeric forms of b-amyloid (Ab) induce a rapid alteration in synaptic plasticity, the process widely believed to underlie learning and memory in the brain [12]. More specifically, Ab causes inhibition of long-term potentiation (LTP) and enhancement of long-term depression (LTD) in the hippocampus [13]. LTD involves the removal of AMPA receptors (AMPARs) from synapses leading to a reduction in synaptic efficiency, and can also result in the shrinkage and elimination of synapses [14]. Therefore, a shift in favour of LTD may lead to neurodegeneration. That such processes may be causally related to neurodegeneration in AD is suggested by the finding that key molecules that are associated with this disorder, such as glycogen synthase kinase (GSK)-3b and caspase-3, are required for the induction of LTD in the hippocampus [15 18] and mediate the Ab inhibition of LTP [19]. Interestingly, recent evidence has shown that Ab inhibition of LTP is absent in the tau knockout (KO) mouse [20]. These data, together with the observation that GSK-3b directly phosphorylates tau [15,18], suggest that tau may be a downstream effector of GSK-3b in LTD. Therefore, we decided to examine the role of tau in LTD in the hippocampus. In this study, we found that in tau KO mice there is a loss of LTD, whereas LTP is not affected. Furthermore, knockdown of tau in hippocampal slices resulted in a complete loss of LTD in the absence of any direct discernible effects on synaptic transmission. We found that LTD was associated with the phosphorylation of tau by GSK-3b [18]. Collectively, these data suggest that tau phosphorylation is an essential component of LTD. 2. Results (a) Long-term depression is absent in MAPT/ and MAPT / mice The physiological role of tau in the hippocampus was initially investigated using tau KO mice. We compared long-term synaptic plasticity in adult (7 11 months old) MAPT/, MAPT/ and MAPT / mice. Because the tau kinase GSK-3b is required for LTD in the hippocampus [17], the primary focus of our investigation was on this form of synaptic plasticity. Field excitatory postsynaptic potentials (fEPSPs) were evoked in area CA1 of anaesthetized mice in response to electrical stimulation of the ipsilateral Schaffer collateral commissural pathway. We found no differences in synaptic transmission between MAPT/, MAPT/ and MAPT / mice, as assessed using input output curves (figure 1a), and we observed no significant differences in paired-pulse facilitation over a range of interstimulus (...truncated)