β-Amyloid Inhibits E-S Potentiation through Suppression of Cannabinoid Receptor 1-Dependent Synaptic Disinhibition

Orr, Adrienne; Hanson, Jesse E.; Liu, Dong; Klotz, Adam; Wright, Sarah; Seubert, Peter; Madison, Daniel V.

doi:10.1016/j.neuron.2014.04.039

Cited by 30 publications

(33 citation statements)

References 79 publications

(136 reference statements)

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“…2C). Our findings are consistent with a recent report that synthetic Aβ 42 impairs LTP of PS (Orr et al, 2014), but our naturally secreted human oAβ species (7PA2 CM) and our pure, synthetic Aβ 40 -S26C dimers/oligomers each also blocked fEPSP LTP. There is evidence that hyperactive neurons in cortical circuits of hAPP/PS1 transgenic mice are associated with decreased GABAergic inhibition (Busche et al, 2008).…”

Section: Discussionsupporting

confidence: 93%

“…On the other hand, reducing GABAergic tone favors increased excitability, as some reports have shown that neuronal hyperactivity is associated with decreased GABAergic inhibition, and GABA administration significantly improved cognitive function in APP Tg mice (Busche et al, 2008; Sun et al, 2012). Recent findings also suggest that Aβ-mediated synaptic suppression occurs in part through inhibition of the GABA A receptor (Orr et al, 2014). These results suggest that oAβ can interrupt glutamate uptake, increase extracellular glutamate levels and thereby activate extrasynaptic GluN2B receptors, and can also reduce GABA A receptor-mediated inhibition, thus promoting neuronal hyperexcitability.…”

Section: Introductionmentioning

confidence: 99%

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Soluble Aβ oligomers impair hippocampal LTP by disrupting glutamatergic/GABAergic balance

Lei

et al. 2016

Neurobiology of Disease

122

107

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Epileptic activity may be more prevalent in early stage Alzheimer’s disease (AD) than previously believed. Several studies report spontaneous seizures and interictal discharges in mouse models of AD undergoing age-related Aβ accumulation. The mechanism by which Aβ-induced neuronal excitability can trigger epileptiform activity remains unknown. Here, we systematically examined field excitatory postsynaptic potentials in stratum radiatum and population spikes in the adjacent stratum pyramidale of CA1 in wild-type mouse hippocampal slices. Soluble Aβ oligomers (oAβ) blocked hippocampal LTP and EPSP-spike (E-S) potentiation, and these effects were occluded by prior treatment with the glutamate uptake inhibitor TBOA. In accord, oAβ elevated glutamate levels in the hippocampal slice medium. Recording population spikes (PS) revealed that oAβ increased PS frequency and reduced LTP, and the latter effect was occluded by pretreatment with the GABAA antagonist picrotoxin. Whole-cell recordings showed that oAβ significantly increased spontaneous EPSC frequency. Decreasing neuronal activity by increasing GABA tone or partially blocking NMDAR activity prevented oAβ impairment of hippocampal LTP. Finally, treating slices with two antiepileptic drugs rescued the LTP inhibition induced by oAβ. We conclude that soluble Aβ oligomers at the low nanomolar levels present in AD brain increase neuronal excitability by disrupting glutamatergic/GABAergic balance, thereby impairing synaptic plasticity.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Soluble Aβ oligomers impair hippocampal LTP by disrupting glutamatergic/GABAergic balance

Lei

et al. 2016

Neurobiology of Disease

122

107

View full text Add to dashboard Cite

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“…These results suggest that natural cannabinoids alter the imbalance of excitatory versus inhibitory neural activity in the somatosensory cortex of aged A␤PP/PS1 mice [24,25]. In fact, A␤ has been demonstrated to inhibit long-term plasticity processes associated with learning and memory through suppression of CB 1 -dependent GABAergic synaptic disinhibition [26]. Moreover, CB 1 receptor activity in GABAergic neurons protects against agedependent cognitive decline [27].…”

Section: Discussionmentioning

confidence: 95%

Delineating the Efficacy of a Cannabis-Based Medicine at Advanced Stages of Dementia in a Murine Model

Aso

Andrés‐Benito

Ferrer

2016

JAD

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Abstract. Previous reports have demonstrated that the combination of 9 -tetrahydrocannabinol ( 9 -THC) and cannabidiol (CBD) botanical extracts, which are the components of an already approved cannabis-based medicine, reduce the Alzheimerlike phenotype of A␤PP/PS1 transgenic mice when chronically administered during the early symptomatic stage. Here, we provide evidence that such natural cannabinoids are still effective in reducing memory impairment in A␤PP/PS1 mice at advanced stages of the disease but are not effective in modifying the A␤ processing or in reducing the glial reactivity associated with aberrant A␤ deposition as occurs when administered at early stages of the disease. The present study also demonstrates that natural cannabinoids do not affect cognitive impairment associated with healthy aging in wild-type mice. The positive effects induced by 9 -THC and CBD in aged A␤PP/PS1 mice are associated with reduced GluR2/3 and increased levels of GABA-A Rα1 in cannabinoid-treated animals when compared with animals treated with vehicle alone.

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“…In addition, eCB-iLTD is involved the potentiation of excitatory postsynaptic potential (EPSP)-spike coupling (E-S coupling) (Chevaleyre and Castillo, 2003). Intriguingly, exogenous application of β–amyloid peptide (Aβ 1–42 ), whose accumulation occurs in Alzheimer’s disease, prevents eCB-mediated disinhibition and subsequent ES coupling potentiation presumably by interfering with CB 1 signaling (Orr et al, 2014). Although the downstream targets remain to be elucidated, this action of Aβ on eCB signaling represents a mechanism that could underlie the cognitive decline in Alzheimer’s disease.…”

Section: Ecb Signaling At Hippocampal and Neocortical Synapsesmentioning

confidence: 99%

Synaptic functions of endocannabinoid signaling in health and disease

et al. 2017

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Endocannabinoids (eCBs) are a family of lipid molecules that act as key regulators of synaptic transmission and plasticity. They are synthetized “on demand” following physiological and/or pathological stimuli. Once released from postsynaptic neurons, eCBs typically act as retrograde messengers to activate presynaptic type 1 cannabinoid receptors (CB1) and induce short- or long-term depression of neurotransmitter release. Besides this canonical mechanism of action, recent findings have revealed a number of less conventional mechanisms by which eCBs regulate neural activity and synaptic function, suggesting that eCB-mediated plasticity is mechanistically more diverse than anticipated. These mechanisms include non-retrograde signaling, signaling via astrocytes, participation in long-term potentiation, and the involvement of mitochondrial CB1. Focusing on paradigmatic brain areas, such as hippocampus, striatum, and neocortex, we review typical and novel signaling mechanisms, and discuss the functional implications in normal brain function and brain diseases. In summary, eCB signaling may lead to different forms of synaptic plasticity through activation of a plethora of mechanisms, which provide further complexity to the functional consequences of eCB signaling.

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β-Amyloid Inhibits E-S Potentiation through Suppression of Cannabinoid Receptor 1-Dependent Synaptic Disinhibition

Cited by 30 publications

References 79 publications

Soluble Aβ oligomers impair hippocampal LTP by disrupting glutamatergic/GABAergic balance

Soluble Aβ oligomers impair hippocampal LTP by disrupting glutamatergic/GABAergic balance

Delineating the Efficacy of a Cannabis-Based Medicine at Advanced Stages of Dementia in a Murine Model

Synaptic functions of endocannabinoid signaling in health and disease

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