Tau-Mediated NMDA Receptor Impairment Underlies Dysfunction of a Selectively Vulnerable Network in a Mouse Model of Frontotemporal Dementia

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.

Tau neurotoxicity and rescue in animal models of human Tauopathies

“…depletion of synaptic vesicle pool) and function of the mossy fibers, which also affected postsynaptic neurons [41]. Mice expressing the V337M mutant of Tau showed an NMDA receptor hypofunction, and pathology could be prevented by the NMDAR co-agonist cycloserine [42]. These and previous studies (for review see e.g.…”

Early-Onset Network Hyperexcitability in Presymptomatic Alzheimer’s Disease Transgenic Mice Is Suppressed by Passive Immunization with Anti-Human APP/Aβ Antibody and by mGluR5 Blockade

“…It was shown that a transgenic mouse model overexpressing mutant human tau exhibits spontaneous epileptic activity and seizures with spike-wave complexes in the EEG recordings, and a higher sensitivity to PTZ (García-Cabrero et al, 2013). Additionally, reduction of endogenous tau was shown to ameliorate network hyperexcitability and cognitive impairment in transgenic APP mice (Roberson et al, 2007, 2011; Warmus et al, 2014; Hall et al, 2015). Conversely, a recent study showed that hyperphosphorylated tau reduces hippocampal CA1 neuronal hyperexcitability via relocation of the axon initial segment down the axon in P301L tau transgenic mice (Hatch et al, 2017).…”

Evaluating Behavior in Mouse Models of the Behavioral Variant of Frontotemporal Dementia: Which Test for Which Symptom?

“…The elevated plus maze has been used in a PGRN deficiency, a CHMP2B mutant and a tau-based mutant transgenic model of bvFTD. In these three studies, mice spent more time in the open arms, showing a disinhibited behavior [29,30,31]. The light/dark box test showed opposite results in two studies based on mice expressing two different tau mutations (P301L and R406W): one line showed disinhibited behavior [32], and the other showed no defect [33].…”

“…It is used as a test of motivation in depression studies [42]. Recently, this test has been used in a study describing deficits in nest building in mice expressing a tau mutant [31]. …”

“…These behaviors can be evaluated by a recording of a spontaneous occurrence in the home cage or in an open field. Recently, excessive grooming has been reported in a tau mutant and in a CHMP2B mutant FTD model [30,31]. …”