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Acid-Sensing Ion Channels and Synaptic Plasticity: A Revisit
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Ming-Gang Liu, Michael X. Zhu, Tian-Le Xu
In the NAc, not only does ASIC1a directly contribute to synaptic transmission, but also it regulates glutamate receptor function by eliciting changes in AMPA/NMDA ratio and miniature EPSCs (mEPSCs). Specifically, the loss of ASIC1a causes an increase in GluA2-lacking AMPA receptors and AMPA/NMDA ratio, which is accompanied by an increased frequency of mEPSCs. All these alterations can be restored by overexpressing ASIC1a in the NAc, which also rescues the cocaine-conditioned place preference56. Consistent with the results in NAc, our recent work in the dorsal striatum also revealed an increased AMPA/NMDA ratio, mainly due to decreased NMDA receptor expression, in excitatory synaptic transmission by ASIC1a disruption, while re-introduction of ASIC1a in the knockout mice can rescue the defect in glutamate receptor expression and function55. Collectively, these observations add strength to the assertion that ASICs are the main postsynaptic proton receptors that can either mediate or modulate synaptic transmission in the brain.
Nerve Agent–Induced Seizures and Status Epilepticus: Neuroprotective Strategies
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Frederic Doreu, Karine Thibault, Nina Dupuis
As presented earlier, it is generally thought that NA-induced SRBD is mainly due to the unregulated activity of the excitatory neurotransmitter Glu. While ACh is not cytotoxic by itself (Sloviter and Dempster, 1985), Glu-induced excitotoxicity has been well recognized since the 1960s (e.g., with the work of Olney and collaborators). Under repetitive depolarization, Glu is released in excess and overstimulates its various receptors. These can either be ionotropic, such as the NMDA, AMPA, or kainate receptors, or metabotropic receptors. To date, although the molecular basis of Glu toxicity remains uncertain, there is a general agreement that NMDA receptors or GluA2-containing AMPA-R, which show higher calcium permeability, play a key role in mediating at least some aspects of Glu neurotoxicity (e.g., Gardoni and Di Luca, 2006; Kew and Kemp, 2005; Noda, 2016). The resulting intracellular calcium overload is particularly important, as it induces supplementary depolarization and overactivation of enzymes (lipases, proteases, endonucleases, kinases, and phosphatases) that can directly damage cell membranes, cytoskeleton, or the structure and functions of organelles (e.g., mitochondria) (Deshpande et al., 2010, 2014, 2016b) or promote oxidative stress (Gupta et al., 2001; Pazdernik et al., 2001; Zaja-Milatovic et al., 2009) or inflammation (de Araujo Furtado et al., 2012; Dhote et al., 2007, 2012; Garrett et al., 2013; Svensson et al., 2005, 2001; Williams et al., 2003). All these events can eventually lead to cell death.
Aging Epigenetics
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Vasily V. Ashapkin, Lyudmila I. Kutueva, Boris F. Vanyushin
Comparative studies of age-related methylation patterns in various tissues showed these patterns to be highly tissue specific. Nevertheless, there are some loci that have methylation levels significantly correlated with age in various tissues. Obviously, these common methylated loci are of the highest relevance to the mechanisms of aging per se, and their methylation status could be used as an epigenetic signature to estimate the biological age. The first non-cell-type-dependent epigenetic aging signature was elaborated based on the DNA methylation datasets from several independent studies that used the Illumina HumanMethylation27 BeadChip platform [33]. Of more than 450 age-correlated CpG sites found, most were hypermethylated with age and only 25 were hypomethylated. This is in accord with the view noted above that hypermethylation at specific sites is a predominant trend upon aging, whereas hypomethylation seems to be less stringently regulated. Most accurate age predictions were obtained when a set of four hypermethylated loci, TRIM58, KCNQ1DN, NPTX2, and GRIA2, has been used. To further enhance the prediction accuracy, a hypomethylated locus BIRC4BP was added to the set. When all five loci were used, the average prediction accuracy across all datasets was ±12.7 years, whereas the use of only the three most reliable of them (NPTX2, GRIA2, and KCNQ1DN) enhanced the accuracy to ±11.4 years. It should be noted that, in the work described, the age prediction was applicable to various tissues and was gender independent, whereas in the previous study described above [32], the prediction was based only on the saliva samples. When the blood samples were investigated, the set of CpG loci with a high predictive capability could be narrowed down to just three (ITGA2B, ASPA, and PDE4C), and the accuracy of age prediction was ±4.5 years [34].
Transcriptomic profiling as biological markers of depression – A pilot study in unipolar and bipolar women
Published in The World Journal of Biological Psychiatry, 2021
Monika Dmitrzak-Weglarz, Aleksandra Szczepankiewicz, Janusz Rybakowski, Paweł Kapelski, Karolina Bilska, Maria Skibinska, Edyta Reszka, Monika Lesicka, Ewa Jablonska, Edyta Wieczorek, Ewelina Bukowska-Olech, Joanna Pawlak
Specific down-regulated pathways for BDI were as follows: glutamatergic synapse (hsa04724), retrograde endocannabinoid signalling (hsa04723), axon guidance (hsa04360), calcium signalling pathway (hsa04020), nicotine addiction (hsa05033), PI3K-Akt signalling pathway (hsa04151), drug metabolism – cytochrome P450 (hsa00982), and morphine addiction (hsa05032). Three genes were the most frequently involved in the pathways mentioned above: glutamate ionotropic receptor AMPA type subunit 2(GRIA2), gamma-aminobutyric acid type A receptor alpha2 subunit(GABRA2), and gamma-aminobutyric acid type A receptor beta1 subunit(GABRB1). Decreased expression of these subunits may reduce the number of functional glutamatergic receptors and cause increased glutamate levels in body fluids and tissues in patients with affective disorders, especially in BDII (King et al. 2019).
Ionotropic glutamate receptors in platelets: opposing effects and a unifying hypothesis
Published in Platelets, 2021
Maggie L. Kalev-Zylinska, Marie-Christine Morel-Kopp, Christopher M. Ward, James I. Hearn, Justin R. Hamilton, Anna Y. Bogdanova
The GRIA2 mRNA is often edited at the Q/R site encoding the apex of a reentrant M2 loop rendering these receptors Ca2+-impermeable (Figure 1A and C) [18]. AMPAR subunits have a low affinity for glutamate, 200–500 μM. In the synaptic cleft, such concentrations arise after the release of vesicular glutamate, to which AMPAR are the first to respond (Figure 1D). When glutamate binds to more than one subunit, AMPAR undergo a conformational change resulting in the opening of the channel pore. AMPAR mediate Na+ influx, which leads to plasma membrane depolarization from the resting membrane potential of approximately −70 mV in neurons and −60 to −70 mV in platelets [32,33]. The AMPAR signal is brief (<10 ms) due to rapid desensitization of the receptor (Figure 1D). AMPAR interact with multiple scaffolding and accessory proteins, including transmembrane AMPAR regulatory proteins (TARP) and glutamate receptor-interacting protein 1 (GRIP1) that modulate its downstream effects [2,34], including in platelets [35] (Table I).
Stress-induced expression pattern of glutamate signaling genes associated with anhedonia
Published in Stress, 2020
Nikolay N. Dygalo, Tatyana S. Kalinina, Galina T. Shishkina
Short-term FS did not induce the core symptom of depression, anhedonia. Nevertheless, this FS caused changes in the expression of one-to-five glutamatergic genes from eleven genes investigated in each brain region. The largest number of these changes occurred in the amygdala that is in consonance with multiple data on the important contribution of glutamatergic neurotransmission in amygdala to behavioral and autonomic stress responses (Wilson et al., 2015). Rare changes in expression of glutamatergic genes in other structures are consistent with published data on the absence of significant short-term stress effects on the expression of many of these genes in the brain. One- or two-days FS did not change gria1 or gria2 expression in the mice hippocampus (Freudenberg, 2019). The enhance in glutamatergic transmission in the prefrontal cortex found in some studies after acute stress may be related to the increased surface expression of NMDA and AMPA receptors subunits (Yuen et al., 2009).