Harney, S. C., Rowan, M. & Anwyl, R. Long-term depression of NMDA receptor-mediated synaptic transmission is dependent on activation of metabotropic glutamate receptors and is altered to long-term potentiation by low intracellular calcium buffering. J. Neurosci. 26, 1128-1132
Department of Pharmacology and Therapeutics, Trinity College Dublin, Dublin, Leinster, IrelandThe Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 02/2006; 26(4):1128-32. DOI: 10.1523/JNEUROSCI.2753-05.2006
Synaptic plasticity of NMDA receptor (NMDAR)-mediated transmission was investigated in the rat dentate gyrus in vitro. Isolated NMDAR EPSCs were recorded from granule cells of the dentate gyrus in response to stimulation of the medial perforant path. Long-term potentiation (LTP) or long-term depression (LTD) of NMDAR EPSCs was observed in response to brief high-frequency stimulation (HFS), with the direction and extent of plasticity dependent on the concentration and type (EGTA vs BAPTA) of the intracellular Ca2+ buffer. LTD was induced in higher concentrations of EGTA and BAPTA than LTP, and BAPTA was approximately 100-fold more potent than EGTA. Although LTD was induced in a high concentration of EGTA (10 mM), a high concentration of BAPTA (10 mM) blocked both LTP and LTD. LTP of AMPA receptor (AMPAR)-EPSCs exhibited a lower dependency on Ca2+ buffering than LTP of NMDAR EPSCs, because LTP of AMPAR EPSCs was induced by HFS in high EGTA (10 mM). We also identified a role for metabotropic glutamate receptor 5 (mGluR5) in NMDAR plasticity. HFS LTD was blocked by the group I/II mGluR antagonist LY341495 ((2S)-2-amino-2-[(1S, 2S)-2-carboxycycloprop-1-yl]-3(xanth-9-yl)propanoic acid) and by the mGluR5-selective antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP). Similarly, low-frequency stimulation-induced LTD of NMDAR EPSCs was also blocked by MPEP. These findings suggest that the direction of plasticity of NMDARs is determined by the intracellular free Ca2+ concentration and is dependent on activation of mGluR5.
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- "The excess of glutamate is taken up by the glial cells through excitatory amino acid transporters . NMDA receptor activation is involved in long term potentiation (LTP) and long term depression (LTD) . "
ABSTRACT: Oxidative stress plays an important role in both initiation and progression of neurodegenerative diseases, such as Alzheimer and Parkinson. Therefore, much attention has been paid to antioxidants for developing therapeutic strategies for the neurodegenerative diseases. However, as serious adverse effects are related to synthetic antioxidants, recent research has been focused on natural products especially phenolic antioxidants. In the present article, we critically review the available literature related to the beneficial role of ferulic acid on Alzheimer's disease, since it is a natural antioxidant which is widely found in different fruits and vegetables. We also provide some information about sources, chemical structure, bioavailability and clinical impacts of ferulic acid.
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- "The cellular and molecular mechanisms underpinning the neurotoxic effect of A oligomers remain elusive but different molecules have been shown to be implicated in this cascade of events leading to synapse and neuronal loss. The potentiation or depression of synapse activity following cell stimulation depends in part on the level of calcium (Ca 2+ ) influx through the N-methyl-Daspartate (NMDA) receptors and/or the activation of the metabotropic glutamate receptors (mGluRs)    . High entry of Ca 2+ through the NMDA receptors has been shown to induce long-term potentiation (LTP), an electrophysiological correlate of memory formation     . "
ABSTRACT: The neurodegenerative process that defines Alzheimer's disease (AD) is initially characterized by synaptic alterations followed by synapse loss and ultimately cell death. Decreased synaptic density that precedes neuronal death is the strongest pathological correlate of cognitive deficits observed in AD. Substantial synapse and neuron loss occur early in disease progression in the entorhinal cortex (EC) and the CA1 region of the hippocampus, when memory deficits become clinically detectable. Mounting evidence suggests that soluble amyloid-β (Aβ) oligomers trigger synapse dysfunction both in vitro and in vivo. However, the neurodegenerative effect of Aβ species observed on neuronal culture or organotypic brain slice culture has been more challenging to mimic in animal models. While most of the transgenic mice that overexpress Aβ show abundant amyloid plaque pathology and early synaptic alterations, these models have been less successful in recapitulating the spatiotemporal pattern of cell loss observed in AD. Recently we developed a novel animal model that revealed the neurodegenerative effect of soluble low-molecular-weight Aβ oligomers in vivo. This new approach may now serve to determine the molecular and cellular mechanisms linking soluble Aβ species to neurodegeneration in animals. In light of the low efficiency of AD therapies based on the amyloid cascade hypothesis a novel framework, the aging factor cascade hypothesis, is proposed in attempt to integrate the new data and concepts that emerged from recent research to develop disease modifying therapies.
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- "). Aβ can act as an extracellular scaffold for mGluR5, leading to an increased clustering of mGluR5 in synapses accompanied by an increased concentration of intracellular calcium . Hence, it is possible that Aβ dependent synaptic depression involves the co-activation of NMDA-receptors and mGluR5. "
ABSTRACT: Alzheimer disease is characterized by a gradual decrease of synaptic function and, ultimately, by neuronal loss. There is considerable evidence supporting the involvement of oligomeric amyloid-beta (Aβ) in the etiology of Alzheimer's disease. Historically, AD research has mainly focused on the long-term changes caused by Aβ rather than analyzing its immediate effects. Here we show that acute perfusion of hippocampal slice cultures with oligomeric Aβ depresses synaptic transmission within 20 minutes. This depression is dependent on synaptic stimulation and the activation of NMDA-receptors, but not on NMDA-receptor mediated ion flux. It, therefore, appears that Aβ dependent synaptic depression is mediated through a use-dependent metabotropic-like mechanism of the NMDA-receptor, but does not involve NMDA-receptor mediated synaptic transmission, i.e. it is independent of calcium flux through the NMDA-receptor.
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