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Title | Tau-mediated NMDA receptor impairment underlies dysfunction of a selectively vulnerable network in a mouse model of frontotemporal dementia. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Warmus BA, Sekar DR, McCutchen E, Schellenberg GD, Roberts RC, McMahon LL, Roberson ED |
Journal | J Neurosci |
Volume | 34 |
Issue | 49 |
Pagination | 16482-95 |
Date Published | 2014 Dec 03 |
ISSN | 1529-2401 |
Keywords | Action Potentials, Aging, Animals, Behavior, Animal, Brain, Cycloserine, Disease Models, Animal, Disks Large Homolog 4 Protein, Excitatory Amino Acid Agonists, Excitatory Postsynaptic Potentials, Frontotemporal Dementia, Guanylate Kinases, Humans, Membrane Proteins, Mice, Mice, Transgenic, Mutation, Neurons, Post-Synaptic Density, Receptors, N-Methyl-D-Aspartate, tau Proteins |
Abstract | Frontotemporal dementia (FTD) is a neurodegenerative behavioral disorder that selectively affects the salience network, including the ventral striatum and insula. Tau mutations cause FTD, but how mutant tau impairs the salience network is unknown. Here, we address this question using a mouse model expressing the entire human tau gene with an FTD-associated mutation (V337M). Mutant, but not wild-type, human tau transgenic mice had aging-dependent repetitive and disinhibited behaviors, with synaptic deficits selectively in the ventral striatum and insula. There, mutant tau depleted PSD-95, resulting in smaller postsynaptic densities and impaired synaptic localization of NMDA receptors (NMDARs). In the ventral striatum, decreased NMDAR-mediated transmission reduced striatal neuron firing. Pharmacologically enhancing NMDAR function with the NMDAR co-agonist cycloserine reversed electrophysiological and behavioral deficits. These results indicate that NMDAR hypofunction critically contributes to FTD-associated behavioral and electrophysiological alterations and that this process can be therapeutically targeted by a Food and Drug Administration-approved drug. |
DOI | 10.1523/JNEUROSCI.3418-14.2014 |
Alternate Journal | J. Neurosci. |
PubMed ID | 25471585 |
PubMed Central ID | PMC4252555 |
Grant List | P30 NS047466 / NS / NINDS NIH HHS / United States P30 NS057098 / NS / NINDS NIH HHS / United States R01NS075487 / NS / NINDS NIH HHS / United States P30NS057098 / NS / NINDS NIH HHS / United States P01 AG017586 / AG / NIA NIH HHS / United States F30AG046088 / AG / NIA NIH HHS / United States P01AG017586 / AG / NIA NIH HHS / United States R01 NS075487 / NS / NINDS NIH HHS / United States T32GM008361 / GM / NIGMS NIH HHS / United States F30 AG046088 / AG / NIA NIH HHS / United States P30NS047466 / NS / NINDS NIH HHS / United States T32 GM008361 / GM / NIGMS NIH HHS / United States |