Different modes of synaptic and extrasynaptic NMDA receptor alteration in the hippocampus of P301S tau transgenic mice. (4th September 2022)

• Record Type: Journal Article
• Authors: Alfaro‐Ruiz, Rocío; Aguado, Carolina; Martín‐Belmonte, Alejandro; Moreno‐Martínez, Ana Esther; Merchán‐Rubira, Jesús; Hernández, Félix; Ávila, Jesús; Fukazawa, Yugo; Luján, Rafael
• Is Part Of: Brain pathology. Volume 33:Number 1(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-09-04
• Subjects: AD mouse model -- Alzheimer disease -- electron microscopy -- freeze‐fracture -- hippocampus -- immunohistochemistry -- NMDA receptors; Nervous system -- Diseases -- Periodicals; Brain -- Diseases -- Periodicals; Neurology -- Periodicals; Brain Diseases -- Periodicals; Cerveau -- Maladies -- Périodiques; Système nerveux -- Maladies -- Périodiques; Neurologie -- Périodiques; 616.805
• DOI: 10.1111/bpa.13115
• Languages: English
• ISSNs: 1015-6305

Abstract

Abstract: 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. Abstract : Differential alteration of synaptic versus extrasynaptic NMDARs in P301S mice . Reduced density of synaptic NMDARs in excitatory synapses in the hippocampus of P301S mice at 10 months. NMDARs at excitatory synapses established on pyramidal cell spines and interneurons are significantly reduced in the CA1 region of the hippocampus compared to age‐matched wild type controls. However, extrasynaptic NMDARs were unaltered, thus producing an imbalance between synaptic and extrasynaptic NMDARs that may contribute to the pathological alterations of P301S mice.