Different modes of synaptic and extrasynaptic <scp>NMDA</scp> receptor alteration in the hippocampus of <scp>P301S</scp> tau transgenic mice

Alfaro-Ruiz, Rocío; Aguado, Carolina; Martín-Belmonte, Alejandro; Moreno-Martínez, Ana Esther; Merchán-Rubira, Jesús; Hernández, Félix; Ávila, Jesús; Fukazawa, Yugo; Luján, Rafael

doi:10.1111/bpa.13115

Cited by 6 publications

(2 citation statements)

References 96 publications

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“…Additionally, accumulation of presynaptic Tau, amyloid-beta oligomers, impaired inhibitory interneuron and glial function or genetic risk factors may contribute to synaptic dysfunction in Alzheimer’s disease 3 . Notably, however, Tau reduction strongly reduces hyperexcitability in AD mouse lines, induced seizure models, and genetic in vivo models of epilepsy 51 , suggesting a critical role of Tau in synaptic dysfunction. Consistent with this hypothesis, clearance of postsynaptic Tau improved cognition in a tauopathy mouse model 32 .…”

Section: Discussionmentioning

confidence: 99%

Multivalent Tau/PSD-95 interactions arrest in vitro condensates and clusters mimicking the postsynaptic density

Shen,

Sun,

Savastano

et al. 2023

Nat Commun

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Alzheimer’s disease begins with mild memory loss and slowly destroys memory and thinking. Cognitive impairment in Alzheimer’s disease has been associated with the localization of the microtubule-associated protein Tau at the postsynapse. However, the correlation between Tau at the postsynapse and synaptic dysfunction remains unclear. Here, we show that Tau arrests liquid-like droplets formed by the four postsynaptic density proteins PSD-95, GKAP, Shank, Homer in solution, as well as NMDA (N-methyl-D-aspartate)-receptor-associated protein clusters on synthetic membranes. Tau-mediated condensate/cluster arrest critically depends on the binding of multiple interaction motifs of Tau to a canonical GMP-binding pocket in the guanylate kinase domain of PSD-95. We further reveal that competitive binding of a high-affinity phosphorylated peptide to PSD-95 rescues the diffusional dynamics of an NMDA truncated construct, which contains the last five amino acids of the NMDA receptor subunit NR2B fused to the C-terminus of the tetrameric GCN4 coiled-coil domain, in postsynaptic density-like condensates/clusters. Taken together, our findings propose a molecular mechanism where Tau modulates the dynamic properties of the postsynaptic density.

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Section: Discussionmentioning

confidence: 99%

Multivalent Tau/PSD-95 interactions arrest in vitro condensates and clusters mimicking the postsynaptic density

Shen,

Sun,

Savastano

et al. 2023

Nat Commun

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“…Recent studies demonstrated that tau is required for the function of extrasynaptic NMDARs [ 64 ] and that they are mostly increased in P301S mice [ 65 ]. In this study, we identified a reduction in both synaptic and extrasynaptic AMPARs in tau pathology in the two main neuronal populations of the CA1 field: pyramidal cells and interneurons.…”

Section: Discussionmentioning

confidence: 99%

Alteration in the Synaptic and Extrasynaptic Organization of AMPA Receptors in the Hippocampus of P301S Tau Transgenic Mice

Alfaro-Ruiz

Aguado

Martín-Belmonte

et al. 2022

IJMS

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Tau pathology is a hallmark of Alzheimer’s disease (AD) and other tauopathies, but how pathological tau accumulation alters the glutamate receptor dynamics driving synaptic dysfunction is unclear. Here, we determined the impact of tau pathology on AMPAR expression, density, and subcellular distribution in the hippocampus of P301S mice using immunoblot, histoblot, and quantitative SDS-digested freeze-fracture replica labeling (SDS-FRL). Histoblot and immunoblot showed differential regulation of GluA1 and GluA2 in the hippocampus of P301S mice. The GluA2 subunit was downregulated in the hippocampus at 3 months while both GluA1 and GluA2 subunits were downregulated at 10 months. However, the total amount of GluA1-4 was similar in P301S mice and in age-matched wild-type mice. Using quantitative SDS-FRL, we unraveled the molecular organization of GluA1-4 in various synaptic connections at a high spatial resolution on pyramidal cell spines and interneuron dendrites in the CA1 field of the hippocampus in 10-month-old P301S mice. The labeling density for GluA1-4 in the excitatory synapses established on spines was significantly reduced in P301S mice, compared to age-matched wild-type mice, in the strata radiatum and lacunosum-moleculare but unaltered in the stratum oriens. The density of synaptic GluA1-4 established on interneuron dendrites was significantly reduced in P301S mice in the three strata. The labeling density for GluA1-4 at extrasynaptic sites was significantly reduced in several postsynaptic compartments of CA1 pyramidal cells and interneurons in the three dendritic layers in P301S mice. Our data demonstrate that the progressive accumulation of phospho-tau is associated with alteration of AMPARs on the surface of different neuron types, including synaptic and extrasynaptic membranes, leading to a decline in the trafficking and synaptic transmission, thereby likely contributing to the pathological events taking place in AD.

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Different modes of synaptic and extrasynaptic NMDA receptor alteration in the hippocampus of P301S tau transgenic mice

et al. 2022

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N‐methyl‐d‐aspartate receptors (NMDARs) are pivotal players in the synaptic transmission and synaptic plasticity underlying learning and memory. Accordingly, dysfunction of NMDARs has been implicated in the pathophysiology of Alzheimer disease (AD). Here, we used histoblot and sodium dodecylsulphate‐digested freeze‐fracture replica labelling (SDS‐FRL) techniques to investigate the expression and subcellular localisation of GluN1, the obligatory subunit of NMDARs, in the hippocampus of P301S mice. Histoblots showed that GluN1 expression was significantly reduced in the hippocampus of P301S mice in a laminar‐specific manner at 10 months of age but was unaltered at 3 months. Using the SDS‐FRL technique, excitatory synapses and extrasynaptic sites on spines of pyramidal cells and interneuron dendrites were analysed throughout all dendritic layers in the CA1 field. Our ultrastructural approach revealed a high density of GluN1 in synaptic sites and a substantially lower density at extrasynaptic sites. Labelling density for GluN1 in excitatory synapses established on spines was significantly reduced in P301S mice, compared with age‐matched wild‐type mice, in the stratum oriens (so), stratum radiatum (sr) and stratum lacunosum‐moleculare (slm). Density for synaptic GluN1 on interneuron dendrites was significantly reduced in P301S mice in the so and sr but unaltered in the slm. Labelling density for GluN1 at extrasynaptic sites showed no significant differences in pyramidal cells, and only increased density in the interneuron dendrites of the sr. This differential alteration of synaptic versus extrasynaptic NMDARs supports the notion that the progressive accumulation of phospho‐tau is associated with changes in NMDARs, in the absence of amyloid‐β pathology, and may be involved in the mechanisms causing abnormal network activity of the hippocampal circuit.

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Different modes of synaptic and extrasynaptic NMDA receptor alteration in the hippocampus of P301S tau transgenic mice

Cited by 6 publications

References 96 publications

Multivalent Tau/PSD-95 interactions arrest in vitro condensates and clusters mimicking the postsynaptic density

Multivalent Tau/PSD-95 interactions arrest in vitro condensates and clusters mimicking the postsynaptic density

Alteration in the Synaptic and Extrasynaptic Organization of AMPA Receptors in the Hippocampus of P301S Tau Transgenic Mice

Different modes of synaptic and extrasynaptic NMDA receptor alteration in the hippocampus of P301S tau transgenic mice

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