Postsynaptic mechanisms of excitotoxicity: Involvement of postsynaptic density proteins, radicals, and oxidant molecules

Division of Fundamental Neurobiology, University Health Network, Toronto, Ontario, Canada M5T 2S8.
Neuroscience (Impact Factor: 3.36). 12/2008; 158(1):293-300. DOI: 10.1016/j.neuroscience.2008.10.021
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ABSTRACT Traditional models of neuronal excitotoxicity focused on the overactivation of receptors such as the ionotropic N-methyl-D-aspartate (NMDA)-subtype glutamate receptor. Recent developments have shifted focus to downstream neurotoxic signaling molecules with exciting implications to specific strategies for treating excitotoxic disorders. This review outlines these developments and introduces newly emerging evidence implicating the involvement of the melastatin subfamily in anoxic neuronal death. Both of these converge on the production of reactive oxygen species (ROS), including superoxide, nitric oxide (NO) and the oxidant peroxynitrite.

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    • "Genetic ablation of CB1Rs exacerbates the neurodegenerative damage associated with experimental autoimmune encephalomyelitis (EAE), a reliable mouse model of multiple sclerosis (MS), by altering synaptic sensitivity to pro-inflammatory cytokines released by infiltrating immune cells and by activated microglia [10]–[12]. Inflammation leads to neuronal damage also in the human brain, and indeed higher frequency and severity of inflammatory episodes have been associated with accelerated neurodegeneration and disability accumulation in MS [13]–[15], but large inter-individual differences among patients exist. Based on this clinical evidence, we postulated therefore that genetic differences in CB1R expression and function might contribute to differential inflammatory neurodegenerative damage in MS patients, as it occurs in EAE mice. "
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    ABSTRACT: Genetic ablation of type-1 cannabinoid receptors (CB1Rs) exacerbates the neurodegenerative damage of experimental autoimmune encephalomyelitis, the rodent model of multiple sclerosis (MS). To address the role on CB1Rs in the pathophysiology of human MS, we first investigated the impact of AAT trinucleotide short tandem repeat polymorphism of CNR1 gene on CB1R cell expression, and secondly on the inflammatory neurodegeneration process responsible for irreversible disability in MS patients. We found that MS patients with long AAT repeats within the CNR1 gene (≥12 in both alleles) had more pronounced neuronal degeneration in response to inflammatory white matter damage both in the optic nerve and in the cortex. Optical Coherence Tomography (OCT), in fact, showed more severe alterations of the retinal nerve fiber layer (RNFL) thickness and of the macular volume (MV) after an episode of optic neuritis in MS patients carrying the long AAT genotype of CNR1. MS patients with long AAT repeats also had magnetic resonance imaging (MRI) evidence of increased gray matter damage in response to inflammatory lesions of the white matter, especially in areas with a major role in cognition. In parallel, visual abilities evaluated at the low contrast acuity test, and cognitive performances were negatively influenced by the long AAT CNR1 genotype in our sample of MS patients. Our results demonstrate the biological relevance of the (AAT)n CNR1 repeats in the inflammatory neurodegenerative damage of MS.
    PLoS ONE 12/2013; 8(12):e82848. DOI:10.1371/journal.pone.0082848 · 3.23 Impact Factor
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    • "Glutamate is essential for physiological synaptic transmission and plasticity, and is involved in a variety of pathophysiological mechanisms shared by acute and chronic disorders of the central nervous system, including MS [11], [22], [35]–[41]. Long-term potentiation (LTP) of the efficacy of glutamate synapses in unaffected areas is believed to mediate clinical recovery from focal brain lesions [1], [3]–[5], but excessive glutamate transmission is detrimental for neuronal survival, through a process termed excitotoxicity [6], [9]. Considerable overlap exists in the receptor and post-receptor mechanisms required for both LTP and excitotoxicity, and a plasticity-pathology continuum has in fact been proposed based on a plethora of experimental findings [42], [43]. "
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    ABSTRACT: Synaptic transmission and plasticity mediated by NMDA receptors (NMDARs) could modulate the severity of multiple sclerosis (MS). Here the role of NMDARs in MS was first explored in 691 subjects carrying specific allelic variants of the NR1 subunit gene or of the NR2B subunit gene of this glutamate receptor. The analysis was replicated for significant SNPs in an independent sample of 1548 MS subjects. The C allele of rs4880213 was found to be associated with reduced NMDAR-mediated cortical excitability, and with increased probability of having more disability than the CT/TT MS subjects. MS severity was higher in the CC group among relapsing-remitting MS (RR-MS) patients, while primary progressive MS (PP-MS) subjects homozygous for the T allele had more pronounced clinical worsening. Mean time to first relapse, but not to an active MRI scan, was lower in the CC group of RR-MS patients, and the number of subjects with two or more clinical relapses in the first two years of the disease was higher in CC compared to CT/TT group. Furthermore, the percentage of relapses associated with residual disability was lower in subjects carrying the T allele. Lesion load at the MRI was conversely unaffected by the C or T allele of this SNP in RR-MS patients. Axonal and neuronal degeneration at the optical coherence tomography was more severe in the TT group of PP-MS patients, while reduced retinal nerve fiber thickness had less consequences on visual acuity in RR-MS patients bearing the T allele. Finally, the T allele was associated with preserved cognitive abilities at the Rao's brief repeatable neuropsychological battery in RR-MS. Signaling through glutamate NMDARs enhances both compensatory synaptic plasticity and excitotoxic neurodegeneration, impacting in opposite ways on RR-MS and PP-MS pathophysiological mechanisms.
    PLoS ONE 06/2013; 8(6):e67357. DOI:10.1371/journal.pone.0067357 · 3.23 Impact Factor
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    • "Excitotoxicity is a phenomenon driven by excessive synaptic accumulation of glutamate and associated with dysregulation of intraneuronal Ca2+ ([Ca2+]i) homeostasis (Choi, 2005). A major feature of excitotoxicity is the NMDAR/Ca2+-dependent enhanced generation of nitric oxide (NO) and other reactive oxygen species (ROS) [reviewed in Forder and Tymianski (2009) and Szydlowska and Tymianski (2010)]. "
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    ABSTRACT: Huntington's disease (HD) is a neurodegenerative condition characterized by severe neuronal loss in the cortex and striatum that leads to motor and behavioral deficits. Excitotoxicity is thought to be involved in HD and several studies have indicated that NMDA receptor (NMDAR) overactivation can play a role in the selective neuronal loss found in HD. Interestingly, a small subset of striatal neurons (less than 1% of the overall population) is found to be spared in post-mortem HD brains. These neurons are medium-sized aspiny interneurons that highly express the neuronal isoform of nitric oxide synthase (nNOS). Intriguingly, neurons expressing large amounts of nNOS [hereafter indicated as nNOS(+) neurons] show reduced vulnerability to NMDAR-mediated excitotoxicity. Mechanisms underlying this reduced vulnerability are still largely unknown and may shed some light on pathogenic mechanisms involved in HD. One untested possibility is that nNOS(+) neurons possess fewer or less functioning NMDARs. Employing single cell calcium imaging we challenged this hypothesis and found that cultured striatal nNOS(+) neurons show NMDAR-evoked responses that are identical to the ones observed in the overall population of neurons that express lower levels of nNOS [nNOS(-) neurons]. NMDAR-dependent deregulation of intraneuronal Ca(2+) is known to generate high levels of reactive oxygen species of mitochondrial origin (mt-ROS), a crucial step in the excitotoxic cascade. With confocal imaging and dihydrorhodamine (DHR; a ROS-sensitive probe) we compared mt-ROS levels generated by NMDAR activation in nNOS(+) and (-) cultured striatal neurons. DHR experiments revealed that nNOS(+) neurons failed to produce significant amounts of mt-ROS in response to NMDA exposure, thereby providing a potential mechanism for their reduced vulnerability to excitotoxicity and decreased vulnerability in HD.
    Frontiers in Physiology 05/2013; 4:112. DOI:10.3389/fphys.2013.00112 · 3.53 Impact Factor
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