Impaired Expression of GABA Signaling Components in the Alzheimer’s Disease Middle Temporal Gyrus

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(22), P. 8704 - 8704

Published: Nov. 18, 2020

γ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter, playing a central role in regulation of cortical excitability and maintenance excitatory/inhibitory (E/I) balance. Several lines evidence point to remodeling cerebral GABAergic system Alzheimer’s disease (AD), with past studies demonstrating alterations GABA receptor transporter expression, synthesizing enzyme activity focal concentrations post-mortem tissue. AD chronic neurodegenerative disorder poorly understood etiology temporal cortex one earliest regions brain be affected by neurodegeneration. Utilizing NanoString nCounter analysis, we demonstrate here transcriptional downregulation several signaling components human middle gyrus (MTG) AD, including GABAA α1, α2, α3, α5, β1, β2, β3, δ, γ2, γ3, θ subunits GABAB 2 (GABABR2) subunit. In addition this, note upregulation betaine-GABA (BGT1) (GAT2), 67 kDa isoform glutamate decarboxylase (GAD67), enzyme. The functional consequences these changes require further investigation, but such may underlie disruptions E/I balance that are believed contribute cognitive decline AD.

Language: Английский

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Enhancing GABAergic signaling ameliorates aberrant gamma oscillations of olfactory bulb in AD mouse models

Molecular Neurodegeneration, Journal Year: 2021, Volume and Issue: 16(1)

Published: March 4, 2021

Abstract Background Before the deposition of amyloid-beta plaques and onset learning memory deficits, patients with Alzheimer’s disease (AD) experience olfactory dysfunction, typified by a reduced ability to detect, discriminate, identify odors. Rodent models AD, such as Tg2576 APP/PS1 mice, also display impaired olfaction, accompanied aberrant in vivo or vitro gamma rhythms pathway. However, mechanistic relationships between electrophysiological, biochemical behavioral phenomena remain unclear. Methods To address above issues AD models, we conducted measurement local field potential (LFP) combination electro-olfactogram (EOG), whole-cell patch recordings evaluate oscillatory synaptic function pharmacological regulation pathway, particularly bulb (OB). Levels protein involved excitation inhibition OB were investigated western blotting fluorescence staining, while studies assessed olfaction function. Results LFP measurements demonstrated an increase oscillations altered behavior both 3xTg mice at 3–5 months old, i.e. age before plaque formation. Fewer sensory neurons (OSNs) EOG contributed decrease excitatory responses M/T cells, suggesting decreased cells trigger interneuron GABA release indicated paired-pulse ratio (PPR), presynaptic parameter. Postsynaptically, there was compensatory levels A R α1 β3 subunits subsequent higher amplitude inhibitory responses. Strikingly, uptake inhibitor tiagabine (TGB) ameliorated abnormal subunits, therapeutic strategy for early symptoms. These findings reveal increased core indicator prior uncover mechanisms underlying activity OB. Conclusions This study suggests that concomitant dysfunction have important implications diagnosis: particular, awareness GABAergic signaling might aid diagnosis suggest strategies damage AD.

Language: Английский

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Microglia regulate chandelier cell axo-axonic synaptogenesis

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(11)

Published: March 9, 2022

SignificanceChandelier cells (ChCs) are a unique type of GABAergic interneuron that form axo-axonic synapses exclusively on the axon initial segment (AIS) neocortical pyramidal neurons (PyNs), allowing them to exert powerful yet precise control over PyN firing and population output. The importance proper ChC function is further underscored by association connectivity defects with various neurological conditions. Despite this, cellular mechanisms governing synapse formation remain poorly understood. Here, we identify microglia as key regulators axonal morphogenesis AIS synaptogenesis, show disease-induced aberrant microglial activation perturbs synaptic development/connectivity in neocortex. In doing so, such findings highlight therapeutic potential manipulating ensure brain wiring.

Language: Английский

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Functional excitatory to inhibitory synaptic imbalance and loss of cognitive performance in people with Alzheimer’s disease neuropathologic change

Acta Neuropathologica, Journal Year: 2022, Volume and Issue: 145(3), P. 303 - 324

Published: Dec. 20, 2022

Abstract Individuals at distinct stages of Alzheimer’s disease (AD) show abnormal electroencephalographic activity, which has been linked to network hyperexcitability and cognitive decline. However, whether pro-excitatory changes the synaptic level are observed in brain areas affected early AD, if they emergent MCI, is not clearly known. Equally important, it known global E/I imbalances correlate with severity impairment continuum AD. Measuring amplitude ion currents human excitatory inhibitory receptors microtransplanted from hippocampus temporal cortex cognitively normal, mildly impaired AD individuals into surrogate cells, we found regional differences shifts (E/I) current ratio that correlates positively toxic proteins degree pathology, impinges negatively on performance scores. Using these data electrophysiologically anchored analysis synapto-proteome same individuals, identified a group sustaining function those related toxicity. We also an uncoupling between expression for GABAergic signaling underlying larger worse performance. Further transcriptomic situ hybridization datasets independent cohort across confirm balance most recent calibrated composite scores memory, executive function, language visuospatial abilities, as well overall These findings indicate may contribute loss capabilities clinical syndrome.

Language: Английский

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The future of stem cell therapies of Alzheimer’s disease

Ageing Research Reviews, Journal Year: 2022, Volume and Issue: 80, P. 101655 - 101655

Published: June 2, 2022

Language: Английский

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