Gamma-aminobutyric acid A receptors in Alzheimer's disease: highly localized remodeling of a complex and diverse signaling pathway

Kwakowsky, Andrea; Guzmán, Beatriz Calvo‐Flores; Govindpani, Karan; Waldvogel, Henry J.; Faull, Richard L.M.

doi:10.4103/1673-5374.235240

Cited by 41 publications

(36 citation statements)

References 11 publications

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“…It is important to point out that, other potential factors might also contribute to the altered extrasynaptic GABA levels, from changes in GABA uptake and clearance processes. Furthermore, remodeling of GABA A R subunit expression, along with alteration of the expression of GABA transporters (GATs) in the AD brain, may buffer changes in synaptic GABA levels, and ultimately, affect the total levels of extrasynaptic GABA [16][17][18][19][20]. test (* p = 0.0382, ** p = 0.0025; NC n = 4, ACSF-injected n = 4, and Aβ 1-42 -injected n = 5).…”

Section: Resultsmentioning

confidence: 99%

“…Mice from the NC, ACSF-injected and Aβ 1-42 -injected groups were euthanized by cervical dislocation and decapitated at 7 days after Aβ 1-42 injection. The brain was rapidly placed in protective ice-cold ACSF containing (mM): N-methyl-D-glucamine (NMDG) (93), KCl (93), NaH 2 PO 4 (1.2), NaHCO 3 (30), HEPES (20), D-glucose (25), sodium ascorbate (5), thiourea (2), sodium pyruvate (3), MgSO 4 (10) and CaCl 2 (0.5), pH 7.35. Hippocampal slices were cut at 350 µm using a vibratome (Leica VT 12000, Wetzlar, Germany).…”

Section: Slice Preparationmentioning

confidence: 99%

“…Hippocampal slices were cut at 350 µm using a vibratome (Leica VT 12000, Wetzlar, Germany). The slices were incubated in a chamber (GD100, Grant, Cambridge, UK) containing protective ACSF at 34 • C for 12 min and transferred and stored for recovery at 21 • C in a holding chamber in ACSF recording solution containing (mM): NaCl (97), KCl (2.5), NaH 2 PO 4 (1.2), NaHCO 3 (30), HEPES (20), D-glucose (25), sodium ascorbate (5), thiourea (2), sodium pyruvate (3), MgSO 4 (2) and CaCl 2 (2) pH 7.35, in the presence of 3 mM kynurenic acid (K3375, Sigma Aldrich, St. Louis, MO, USA) and 5 µM GABA (A2129, Sigma Aldrich).…”

Section: Slice Preparationmentioning

confidence: 99%

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Amyloid-Beta1-42 -Induced Increase in GABAergic Tonic Conductance in Mouse Hippocampal CA1 Pyramidal Cells

et al. 2020

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Alzheimer’s disease (AD) is a complex and chronic neurodegenerative disorder that involves a progressive and severe decline in cognition and memory. During the last few decades a considerable amount of research has been done in order to better understand tau-pathology, inflammatory activity and neuronal synapse loss in AD, all of them contributing to cognitive decline. Early hippocampal network dysfunction is one of the main factors associated with cognitive decline in AD. Much has been published about amyloid-beta1-42 (Aβ1-42)-mediated excitotoxicity in AD. However, increasing evidence demonstrates that the remodeling of the inhibitory gamma-aminobutyric acid (GABAergic) system contributes to the excitatory/inhibitory (E/I) disruption in the AD hippocampus, but the underlying mechanisms are not well understood. In the present study, we show that hippocampal injection of Aβ1-42 is sufficient to induce cognitive deficits 7 days post-injection. We demonstrate using in vitro whole-cell patch-clamping an increased inhibitory GABAergic tonic conductance mediated by extrasynaptic type A GABA receptors (GABAARs), recorded in the CA1 region of the mouse hippocampus following Aβ1-42 micro injection. Such alterations in GABA neurotransmission and/or inhibitory GABAARs could have a significant impact on both hippocampal structure and function, causing E/I balance disruption and potentially contributing to cognitive deficits in AD.

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Section: Resultsmentioning

confidence: 99%

Section: Slice Preparationmentioning

confidence: 99%

Section: Slice Preparationmentioning

confidence: 99%

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Amyloid-Beta1-42 -Induced Increase in GABAergic Tonic Conductance in Mouse Hippocampal CA1 Pyramidal Cells

et al. 2020

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“…The STG also displayed age-specific GABA A R subunit expression decrease in older males and GAD65 level decrease in older females. Previous literature suggests that GABAR and GAD level alterations may subsequently lead to compensatory changes in order to maintain homeostasis, and this may affect regional network functionality [2–9, 67–69]. This is the first study to explore the sex- and age-specific expression of GABA signaling components in the aforementioned brain regions and to predict the potentially resulting functional alterations.…”

Section: Discussionmentioning

confidence: 95%

Sex- and age-related changes in GABA signaling components in the human cortex

et al. 2019

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Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the nervous system. Previous studies have shown fluctuations in expression levels of GABA signaling components—glutamic acid decarboxylase (GAD), GABA receptor (GABAR) subunit, and GABA transporter (GAT)—with increasing age and between sexes; however, this limited knowledge is highly based on animal models that produce inconsistent findings. This study is the first analysis of the age- and sex-specific changes of the GAD, GABAA/BR subunits, and GAT expression in the human primary sensory and motor cortices; superior (STG), middle (MTG), and inferior temporal gyrus (ITG); and cerebellum. Utilizing Western blotting, we found that the GABAergic system is relatively robust against sex and age-related differences in all brain regions examined. However, we observed several sex-dependent differences in GABAAR subunit expression in STG along with age-dependent GABAAR subunit and GAD level alteration. No significant age-related differences were found in α1, α2, α5, β3, and γ2 subunit expression in the STG. However, we found significantly higher GABAAR α3 subunit expression in the STG in young males compared to old males. We observed a significant sex-dependent difference in α1 subunit expression: males presenting significantly higher levels compared to women across all stages of life in STG. Older females showed significantly lower α2, α5, and β3 subunit expression compared to old males in the STG. These changes found in the STG might significantly influence GABAergic neurotransmission and lead to sex- and age-specific disease susceptibility and progression.

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“…Durante vários anos, acreditava-se que a sinalização de GABA não era particularmente afetada na DA, com alguns estudos iniciais demonstrando preservação dos interneurônios GABAérgicos e outros relatando mudanças inconsistentes e frequentemente contraditórias nos níveis de GABA, atividade da enzima GAD e expressão do receptor GABA no cérebro na condição da DA 22,23 . Nesse sentido, o sistema GABAérgico sofre remodelação significativa no cérebro de pacientes com DA, mas é importante reconhecer se isso é consequência da doença em si ou secundário à neurodegeneração 24 .…”

Section: Introductionunclassified

Receptores neurais e a doença de Alzheimer: uma revisão sistemática da literatura sobre as famílias de receptores mais associadas a doença, suas funções e áreas de expressão

Câmara

2019

J. bras. psiquiatr.

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RESUMO Objetivo O artigo tem como objetivo determinar as famílias de receptores mais estudadas, envolvidas com a doença de Alzheimer, assim como determinar a região do sistema nervoso na qual mais tipos de receptores são expressos e quais funções dos receptores estão predominantemente associadas com a patologia em questão. O artigo busca mostrar os modelos e métodos mais utilizados nessas pesquisas, resumindo alguns achados e discutindo o impacto desses estudos no conhecimento científico. Métodos Esta revisão utilizou-se de uma metodologia sistemática (Prospero; ID 141957). Resultados Pode-se constatar que os receptores de transcrição nuclear foram os mais estudados. A maior parte desses receptores se expressa no córtex cerebral e hipocampo. Adicionalmente, a maioria das pesquisas avaliou os receptores relacionados com os efeitos benéficos na doença. A eliminação da proteína amiloide ou o bloqueio de vias relacionadas à síntese dessa proteína foram as principais funções desempenhadas por esses receptores. Por fim, as técnicas de imunoistoquímica e reação em cadeia de polimerase em tempo real (RT-PCR), respectivamente, foram as mais utilizadas, e os roedores consistiram no principal modelo de estudo. Conclusões Os receptores de transcrição nuclear, o córtex cerebral, o hipocampo, a micróglia e a proteína beta-amiloide mostraram importância na patogênese da doença de Alzheimer neste estudo.

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Gamma-aminobutyric acid A receptors in Alzheimer's disease: highly localized remodeling of a complex and diverse signaling pathway

Cited by 41 publications

References 11 publications

Amyloid-Beta1-42 -Induced Increase in GABAergic Tonic Conductance in Mouse Hippocampal CA1 Pyramidal Cells

Amyloid-Beta1-42 -Induced Increase in GABAergic Tonic Conductance in Mouse Hippocampal CA1 Pyramidal Cells

Sex- and age-related changes in GABA signaling components in the human cortex

Receptores neurais e a doença de Alzheimer: uma revisão sistemática da literatura sobre as famílias de receptores mais associadas a doença, suas funções e áreas de expressão

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