The GABAergic system as a therapeutic target for Alzheimer's disease

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

doi:10.1111/jnc.14345

Cited by 132 publications

(84 citation statements)

References 229 publications

(518 reference statements)

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“…Such a possibility is consistent with data suggesting that impaired GABAergic neurotransmission occurs early in AD and with data from animal studies of AD mouse models demonstrating beneficial effects of GABAergic agonists on cognition (Calvo-Flores et al, 2018). Our ReHo analyses revealed increased synchronous activity in the temporal cortex and AAC, brain regions known to be affected in AD.…”

Section: Discussionsupporting

confidence: 87%

Brain regional synchronous activity predicts tauopathy in 3×TgAD mice

Liu

Stein

et al. 2018

Neurobiology of Aging

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Alzheimer’s disease (AD) is characterized by progressive cognitive impairment and by extensive neuronal loss associated with extracellular amyloid β-peptide (Aβ) plaques and intraneuronal tau pathology in temporal and parietal lobes. AD patients are at increased risk for epileptic seizures, and data from experimental models of AD suggest that aberrant neuronal network activity occurs early in the disease process before cognitive deficits and neuronal degeneration. The contributions of Aβ and/or tau pathologies to dysregulation of neuronal network activity are unclear. Using a transgenic mouse model of AD (3 × TgAD mice) in which there occurs differential age-dependent development of tau and Aβ plaque pathologies, we applied analysis of resting state functional magnetic resonance imaging regional homogeneity, a measure of local synchronous activity, to discriminate the effects of Aβ and tau on neuronal network activity throughout the brain. Compared to age-matched wild-type mice, 6- to 8-month-old 3 × TgAD mice exhibited increased regional homogeneity in the hippocampus and parietal and temporal cortices, regions with tau pathology but not Aβ pathology at this age. By 18–24 months of age, 3 × TgAD mice exhibited extensive tau and Aβ pathologies involving the hippocampus and multiple functionally related brain regions, with a spatial expansion of increased local synchronous activity to include those regions. Our findings demonstrate that age-related brain regional hypersynchronous activity is associated with early tau pathology in a mouse model, consistent with a role for early tau pathology in the neuronal circuit hyperexcitability that is believed to precede and contribute to neuronal degeneration in AD.

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Section: Discussionsupporting

confidence: 87%

Brain regional synchronous activity predicts tauopathy in 3×TgAD mice

Liu

Stein

et al. 2018

Neurobiology of Aging

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“…Consistent with this concept, antiepileptic drugs mainly targeted on the glutamatergic system, such as levetiracetam (Sanchez et al, ), have been used to compensate the excess of excitation, although with limited success (Vossel et al, ). Consequently, inhibitory neurotransmission systems have gained great interest in recent years, not only as potential pharmacological targets, but also as part of combinational therapies that might synergistically protect neuronal degradation in AD (Calvo‐Flores Guzman et al, ; Nava‐Mesa et al, ). One interesting example is the combined drug therapy using the NMDA‐receptor antagonist, acamprosate and the GABA B agonist, baclofen (Hill & Bowery, ) whose main effector is the GirK channel, with significant benefits over monotherapeutics (Chumakov et al, ).…”

Section: Discussionmentioning

confidence: 99%

Hippocampal long‐term synaptic depression and memory deficits induced in early amyloidopathy are prevented by enhancing G‐protein‐gated inwardly rectifying potassium channel activity

Sánchez‐Rodríguez

Djebari

Temprano‐Carazo

et al. 2020

Journal of Neurochemistry

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Hippocampal synaptic plasticity disruption by amyloid-β (Aβ) peptides + thought to be responsible for learning and memory impairments in Alzheimer's disease (AD) early stage.Failures in neuronal excitability maintenance seems to be an underlying mechanism.G-protein-gated inwardly rectifying potassium (GirK) channels control neural excitability by hyperpolarization in response to many G-protein-coupled receptors activation. Here, in early in vitro and in vivo amyloidosis mouse models, we study whether GirK channels take part of the hippocampal synaptic plasticity impairments generated by Aβ 1-42 . In vitro electrophysiological recordings from slices showed that Aβ 1-42 alters synaptic plasticity by switching high-frequency stimulation (HFS) induced long-term potentiation (LTP) to long-term depression (LTD), which led to in vivo hippocampal-dependent memory deficits. Remarkably, selective pharmacological activation of GirK channels with ML297 rescued both HFS-induced LTP and habituation memory from Aβ 1-42 action. Moreover, when GirK channels were specifically blocked by Tertiapin-Q, their activation with ML297 failed to rescue LTP from the HFS-dependent LTD induced by Aβ 1-42 . On the other hand, the molecular analysis of the recorded slices by western blot showed that the expression of GIRK1/2 subunits, which form the prototypical GirK channel in the hippocampus, was not significantly regulated by Aβ 1-42 . However, immunohistochemical examination of our in vivo amyloidosis model showed Aβ 1-42 to down-regulate hippocampal GIRK1 subunit expression. Together, our results describe an Aβ-mediated deleterious synaptic mechanism that modifies the induction threshold for hippocampal LTP/LTD and underlies memory alterations observed in amyloidosis models. In this scenario, GirK activation assures memory formation by preventing the transformation of HFS-induced LTP into LTD. This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Additional supporting information may be found online in the Supporting Information section. How to cite this article: Sánchez-Rodríguez I, Djebari S, Temprano-Carazo S, et al. Hippocampal long-term synaptic depression and memory deficits induced in early amyloidopathy are prevented by enhancing G-protein-gated inwardly rectifying potassium channel activity. J. Neurochem.

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“…Analysis of the indexes for temporal-scale-dependent complexity has shown that this reduction of complexity especially concentrates in fast wave components (34,36). Studies of neurotransmitter changes in AD have reported that dysfunction of the gamma-aminobutyric acid (GABA) signaling system, which is caused by the deposition of amyloid-b and tau proteins, leads to reduced oscillatory gamma band activity (68)(69)(70). The impairment of gamma oscillatory activity might lead the complexity at faster temporal scales more than slower temporal scales (34,36).…”

Section: Discussionmentioning

confidence: 99%

Classification Methods Based on Complexity and Synchronization of Electroencephalography Signals in Alzheimer’s Disease

et al. 2020

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Electroencephalography (EEG) has long been studied as a potential diagnostic method for Alzheimer's disease (AD). The pathological progression of AD leads to cortical disconnection. These disconnections may manifest as functional connectivity alterations, measured by the degree of synchronization between different brain regions, and alterations in complex behaviors produced by the interaction among widespread brain regions. Recently, machine learning methods, such as clustering algorithms and classification methods, have been adopted to detect disease-related changes in functional connectivity and classify the features of these changes. Although complexity of EEG signals can also reflect AD-related changes, few machine learning studies have focused on the changes in complexity. Therefore, in this study, we compared the ability of EEG signals to detect characteristics of AD using different machine learning approaches one focused on functional connectivity and the other focused on signal complexity. We examined functional connectivity, estimated by phase lag index (PLI) in EEG signals in healthy older participants [healthy control (HC)] and patients with AD. We estimated signal complexity using multi-scale entropy. Utilizing a support vector machine, we compared the identification accuracy of AD based on functional connectivity at each frequency band and complexity component. Additionally, we evaluated the relationship between synchronization and complexity. The identification accuracy of functional connectivity of the alpha, beta, and gamma bands was significantly high (AUC 1.0), and the identification accuracy of complexity was sufficiently high (AUC 0.81). Moreover, the relationship between functional connectivity and complexity exhibited various temporal-scale-andregional-specific dependency in both HC participants and patients with AD. In conclusion, the combination of functional connectivity and complexity might reflect complex pathological process of AD. Applying a combination of both machine learning methods

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The GABAergic system as a therapeutic target for Alzheimer's disease

Cited by 132 publications

References 229 publications

Brain regional synchronous activity predicts tauopathy in 3×TgAD mice

Brain regional synchronous activity predicts tauopathy in 3×TgAD mice

Hippocampal long‐term synaptic depression and memory deficits induced in early amyloidopathy are prevented by enhancing G‐protein‐gated inwardly rectifying potassium channel activity

Classification Methods Based on Complexity and Synchronization of Electroencephalography Signals in Alzheimer’s Disease

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