Tau-mediated NMDA receptor impairment underlies dysfunction of a selectively vulnerable network in a mouse model of frontotemporal dementia
| Autor: | Rosalinda C. Roberts, Dheepa R. Sekar, Brian A. Warmus, Gerard D. Schellenberg, Erik D. Roberson, Lori L. McMahon, Eve McCutchen |
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| Rok vydání: | 2014 |
| Předmět: |
Genetically modified mouse
Aging Action Potentials Mice Transgenic tau Proteins Receptors N-Methyl-D-Aspartate Mice Postsynaptic potential mental disorders medicine Excitatory Amino Acid Agonists Animals Humans Neurons Behavior Animal General Neuroscience musculoskeletal neural and ocular physiology Ventral striatum Brain Excitatory Postsynaptic Potentials Membrane Proteins Post-Synaptic Density Articles medicine.disease Disease Models Animal medicine.anatomical_structure nervous system Cycloserine Frontotemporal Dementia Mutation Excitatory postsynaptic potential NMDA receptor Psychology Insula Neuroscience Postsynaptic density Disks Large Homolog 4 Protein Guanylate Kinases psychological phenomena and processes Frontotemporal dementia |
| Zdroj: | The Journal of neuroscience : the official journal of the Society for Neuroscience. 34(49) |
| ISSN: | 1529-2401 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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