Increased excitatory to inhibitory synaptic ratio in parietal cortex samples from individuals with Alzheimer’s disease

Lauterborn, Julie C.; Scaduto, P; Cox, Conor D.; Schulmann, Anton; Lynch, Gary; Gall, Christine M.; Keene, C. Dirk; Limón, Agenor

doi:10.1038/s41467-021-22742-8

Cited by 104 publications

(108 citation statements)

References 75 publications

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“…Whilst it is unlikely that epilepsy is a causative factor in developing AD, there is ample evidence to suggest that pathological changes in AD brain lead to disrupted excitatory/ inhibitory balance. This could involve disruption to inhibitory synapse structure or function, but there is some controversy about the role of inhibitory synapse damage in AD with some studies finding decreases in inhibitory synapse density or function [10][11][12][13][14], some finding increases [15][16][17], some finding a mix of increases/decreases depending on marker or disease stage [18,19] and some finding no change [20,21] (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Inhibitory synapse loss and accumulation of amyloid beta in inhibitory presynaptic terminals in Alzheimer's disease

Kurucu

Colom‐Cadena

Davies

et al. 2021

Euro J of Neurology

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Background and purpose: Synapse degeneration in Alzheimer's disease (AD) correlates strongly with cognitive decline. There is well-established excitatory synapse loss in AD with known contributions of pathological amyloid beta (Aβ) to excitatory synapse dysfunction and loss. Despite clear changes in circuit excitability in AD and model systems, relatively little is known about pathology in inhibitory synapses.Methods: Here human postmortem brain samples (n = 5 control, 10 AD cases) from temporal and occipital cortices were examined to investigate whether inhibitory synapses and neurons are lost in AD and whether Aβ may contribute to inhibitory synapse degeneration. Inhibitory neurons were counted in all six cortical layers using stereology software, and array tomography was used to examine synapse density and the accumulation of Aβ in synaptic terminals.Results: Differing inhibitory neuron densities were observed in the different cortical layers. The highest inhibitory neuron density was observed in layer 4 in both brain regions and the visual cortex had a higher inhibitory neuron density than the temporal cortex.There was significantly lower inhibitory neuron density in AD than in control cases in all six cortical layers. High-resolution array tomography imaging revealed plaque-associated loss of inhibitory synapses and accumulation of Aβ in a small subset of inhibitory presynaptic terminals with the most accumulation near amyloid plaques.Conclusions: Inhibitory neuron and synapse loss in AD may contribute to disrupted excitatory/inhibitory balance and cognitive decline. Future work is warranted to determine whether targeting inhibitory synapse loss could be a useful therapeutic strategy.

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Section: Introductionmentioning

confidence: 99%

Inhibitory synapse loss and accumulation of amyloid beta in inhibitory presynaptic terminals in Alzheimer's disease

Kurucu

Colom‐Cadena

Davies

et al. 2021

Euro J of Neurology

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“…However, new evidence has demonstrated that the GABAergic system, the counterpart of E/I balance and the major inhibitory neurotransmitter system in the central nervous system, is altered significantly and that this contributes to E/I imbalance and further AD pathogenesis [ 1 ]. Lauterborn et al assessed anatomical and electrophysiological synaptic E/I ratios in postmortem parietal cortex samples from middle-aged individuals with AD (early-onset), and revealed significantly elevated E/I ratios for AD, which supported the hypothesis that E/I imbalance contributes to the intellectual decline in AD [ 34 ]. Based on the above evidence, we believe that E/I balance is a critical issue.…”

Section: Discussionmentioning

confidence: 96%

Neurotransmitter-stimulated neuron-derived sEVs have opposite effects on amyloid β-induced neuronal damage

et al. 2021

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The ratio of excitatory to inhibitory neurotransmitters is essential for maintaining the firing patterns of neural networks, and is strictly regulated within individual neurons and brain regions. Excitatory to inhibitory (E/I) imbalance has been shown to participate in the progression of neurodegenerative diseases, including Alzheimer's disease (AD). Glutamate excitotoxicity and GABAergic neuron dysfunction appear to be key components of the neuronal cell death that takes place in AD. Since extracellular vesicles (EVs) are now explored as an important vehicle in transmitting signals between cells, we hypothesized that the function of neuron-derived small EVs (sEVs) might be regulated by the status of neurotransmitter balance and that sEVs might affect amyloid β (Aβ) toxicity on neurons. This study aimed to reveal the effects of sEVs from unbalanced neurotransmitter-stimulated neurons on Aβ-induced toxicity. We demonstrated the opposite effects of the two groups of sEVs isolated from neurons stimulated by glutamate or GABA on Aβ toxicity in vivo and in vitro. The sEVs released from GABA-treated neurons alleviated Aβ-induced damage, while those released from glutamate-treated neurons aggravated Aβ toxicity. Furthermore, we compared the microRNA (miRNA) composition of sEVs isolated from glutamate/GABA/PBS-treated neurons. Our results showed that glutamate and GABA oppositely regulated miR-132 levels in sEVs, resulting in the opposite destiny of recipient cells challenged with Aβ. Our results indicated that manipulating the function of sEVs by different neurotransmitters may reveal the mechanisms underlying the pathogenesis of AD and provide a promising strategy for AD treatment.

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“…Canas et al (2014) detected a predominant loss of glutamatergic terminal markers in a β-amyloid peptide model of AD. Despite severe glutamate synaptic loss, this result would also have significant implications in excitability and activity dependent production of oligomers (Cirrito et al, 2005;Lauterborn et al, 2021). Moreover, the enrichment analysis of CT related genes to cell types was mainly and significantly enriched in "chemical synaptic transmission" and "synaptic transmission, glutamatergic."…”

Section: Discussionmentioning

confidence: 99%

Cortical Thickness Differences Are Associated With Chemical Synaptic Transmission Upregulated Genes in Degeneration of Mild Cognitive Impairment

Cai

Huang

Yang

et al. 2021

Front. Aging Neurosci.

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Mild cognitive impairment (MCI) is a transition between normal cognition (NC) and Alzheimer’s disease (AD). Differences in cortical thickness (ΔCT) have been reported in cases that degenerate from MCI to AD. The aspects of genetic and transcriptional variation related to ΔCT are vague. In this study, using an 8-year longitudinal follow-up outcome, we investigated the genetic correlates of ΔCT in MCI subjects with degeneration from MCI to AD (MCI_AD). We employed partial least squares regression (PLSR) on brain T1-weighted magnetic resonance imaging (MRI) images of 180 participants [143 stable MCI (MCI_S) participants and 37 MCI_AD participants] and brain gene expression data from the Allen Institute for Brain Science (AIBS) database to investigate genes associated with ΔCT. We found that upregulated PLS component 1 ΔCT-related genes were enriched in chemical synaptic transmission. To verify the robustness and specificity of the results, we conducted PLSR analysis invalidation and specificity datasets and performed weighted gene co-expression network analysis instead of PLSR for the above three datasets. We also used gene expression data in the brain prefrontal cortex from the Gene Expression Omnibus (GEO) database to indirectly validate the robustness and specificity of our results. We conclude that transcriptionally upregulated genes involved in chemical synaptic transmission are strongly related to global ΔCT in MCI patients who experience degeneration from MCI to AD.

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Increased excitatory to inhibitory synaptic ratio in parietal cortex samples from individuals with Alzheimer’s disease

Cited by 104 publications

References 75 publications

Inhibitory synapse loss and accumulation of amyloid beta in inhibitory presynaptic terminals in Alzheimer's disease

Inhibitory synapse loss and accumulation of amyloid beta in inhibitory presynaptic terminals in Alzheimer's disease

Neurotransmitter-stimulated neuron-derived sEVs have opposite effects on amyloid β-induced neuronal damage

Cortical Thickness Differences Are Associated With Chemical Synaptic Transmission Upregulated Genes in Degeneration of Mild Cognitive Impairment

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