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Increased excitatory to inhibitory synaptic ratio in parietal cortex samples from individuals with Alzheimer’s disease
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Increased excitatory to inhibitory synaptic ratio in parietal cortex samples from individuals with Alzheimer’s disease
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Journal Article
Increased excitatory to inhibitory synaptic ratio in parietal cortex samples from individuals with Alzheimer’s disease
2021
Overview
Synaptic disturbances in excitatory to inhibitory (E/I) balance in forebrain circuits are thought to contribute to the progression of Alzheimer’s disease (AD) and dementia, although direct evidence for such imbalance in humans is lacking. We assessed anatomical and electrophysiological synaptic E/I ratios in post-mortem parietal cortex samples from middle-aged individuals with AD (early-onset) or Down syndrome (DS) by fluorescence deconvolution tomography and microtransplantation of synaptic membranes. Both approaches revealed significantly elevated E/I ratios for AD, but not DS, versus controls. Gene expression studies in an independent AD cohort also demonstrated elevated E/I ratios in individuals with AD as compared to controls. These findings provide evidence of a marked pro-excitatory perturbation of synaptic E/I balance in AD parietal cortex, a region within the default mode network that is overly active in the disorder, and support the hypothesis that E/I imbalances disrupt cognition-related shifts in cortical activity which contribute to the intellectual decline in AD.
Synaptic loss may disturb the excitatory to inhibitory balance (E/I ratio) in circuits vulnerable in Alzheimer’s disease (AD). The authors find reduced synaptic levels of PSD-95 and gephyrin and show that individuals with AD exhibit a pro-excitatory shift of postsynaptic densities and the electrophysiological synaptic E/I ratio in the parietal cortex.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 14/63
/ 49/31
/ 9/10
/ Age
/ Alzheimer Disease - physiopathology
/ Amyloid beta-Peptides - metabolism
/ Animals
/ Anura
/ Autopsy
/ Circuits
/ Cognitive Dysfunction - metabolism
/ Cognitive Dysfunction - physiopathology
/ Disks Large Homolog 4 Protein - metabolism
/ Down Syndrome - physiopathology
/ Female
/ GABA Plasma Membrane Transport Proteins - genetics
/ GABA Plasma Membrane Transport Proteins - metabolism
/ Gene Expression Regulation - genetics
/ Gene Expression Regulation - physiology
/ Gephyrin
/ Humanities and Social Sciences
/ Humans
/ Male
/ Membrane Proteins - metabolism
/ Parietal Lobe - anatomy & histology
/ Parietal Lobe - physiopathology
/ Postsynaptic density proteins
/ Science
/ Synaptic Membranes - metabolism
