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The Neurobiology of Central Sensitization
Published in Robert M. Bennett, The Clinical Neurobiology of Fibromyalgia and Myofascial Pain, 2020
From these properties it is logical to propose that the lasting enhancement of excitatory synaptic responses at primary afferent-second order synapses in pain pathways shares a common signalling cascade with so-called NMDA receptor-dependent form of long-term potentiation [LTP] of excitatory synaptic transmission that is observed in many regions of the CNS. The mechanisms of NMDA receptor-dependent LTP have been examined in most detail for Schaffer collateral synapses onto CA1 neurons in the hippocampus, where a core signalling cascade for initiating LTP has been proposed (8,9). This requires Ca2+ influx through NMDA receptors during the tetanic stimulation which is accomplished by temporal summation of EPSPs, diminishing the Mg2+ blockade of the channel. Enhancement of NMDA channel function by the tyrosine kinase Src is also necessary and a coincident rise in postsynaptic sodium concentration may additionally contribute to boosting NMDA receptor activity (9). The resultant influx of Ca2+ sets off a cascade leading to activation of Ca2+/calmodulin dependent kinase II [CAMKII] and phosphorylation of the AMPA receptor subunit protein [GluRl] which causes AMPA channels to move to a high conductance state. Phosphorylation of AMPA receptors may also cause increased cell surface expression of AMPA receptors and allows conversion of “silent synapses,” those lacking AMPA receptors, into active ones.
Antiepileptic Drugs
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Perampanel is a one of the first selective, noncompetitive antagonist of the AMPA-type ionotropic glutamate receptor (Bialer and White, 2010; Stephen and Brodie, 2011). Unlike NMDA antagonists, which shorten the duration of repetitive discharges, AMPA receptor antagonists prevent repetitive neuronal firing. Perampanel decreases fast excitatory signaling critical to the seizure generation and spread (Tortorella et al., 1997). Perampanel has more inhibitory effect on seizure propagation than on seizure initiation.
Neurophysiology of Old Neurons and Synapses
Published in David R. Riddle, Brain Aging, 2007
In terms of biochemical markers, there is considerable controversy concerning the level of expression of postsynaptic glutamate receptors in region CA1 (for a review, see [38]). Nevertheless, it is clear that the decrease in synaptic strength is associated with a decrease in the level of depolarization associated with activation of ionotropic alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type glutamate receptors [94, 95]. Studies on the responsiveness of the other major ionotropic glutamate receptor, the N-methyl-D-aspartate receptor (NMDAR), indicate that NMDAR responses are reduced to the same extent as AMPA receptors [116, 117] or are unchanged [95], suggesting a differential contribution of receptor subtypes to synaptic weakening. Importantly, AMPA and NMDA receptors contribute differentially to the induction and expression, respectively, of long-term synaptic plasticity at this synapse.
Efficacy of dextromethorphan for the treatment of depression: a systematic review of preclinical and clinical trials
Published in Expert Opinion on Emerging Drugs, 2021
Amna Majeed, Jiaqi Xiong, Kayla M. Teopiz, Jason Ng, Roger Ho, Joshua D. Rosenblat, Lee Phan, Bing Cao, Roger S. McIntyre
In 2015, the same group of researchers also identified the potential mechanistic contribution of AMPA receptors, finding that DXM’s antidepressant efficacy was impaired by the pre-administration of the AMPA antagonist, NBQX. It is hypothesized that DXM may indirectly alter AMPA activity as it only weakly binds to the receptor [31]. Interestingly, the AMPA receptor-mediated mechanism of DXM is similar to that of ketamine, which is also consistent with the observation that DXM exerts similarly rapid efficacy as ketamine [74]. The upregulation of AMPA receptor activity was implicated in the mechanisms of many other existing antidepressant agents [74,75]. The downstream signaling of AMPA receptors was also observed to increase hippocampal BDNF, markers of hippocampal neurogenesis that are often found to decrease in patients with MDD and BD, and postulated to be critical for effective antidepressant action [76].
Molecular Mechanisms Associated with the Benefits of Variable Practice in Motor Learning
Published in Journal of Motor Behavior, 2020
Tércio Apolinário-Souza, Ana Flávia Santos Almeida, Natália Lelis-Torres, Juliana Otoni Parma, Grace Schenatto Pereira, Guilherme Menezes Lage
To the authors’ knowledge, there is yet no explanation at the molecular level to the benefits of variable practice. The results of our study, associated with others in the literature, enable the formulation of an alternative explanation to account for these benefits. In variable practice, the previous trial is different from the current trial, producing a larger error than constant practice (Broadbent, Causer, Mark Williams, & Ford, 2017). The error of the previous trial slightly benefits the subsequent trial, since the sensory consequences of the previous trial, received and processed in the posterior regions, little refer to the planning of the next trial. Therefore, greater ambiguity is produced when formulating the expectations of the next trial, inducing the learner’s system to increase the transmission of signals inter cerebral regions (Fuster, 2006, 2017). Increased synaptic transmission leads to increased pre-synaptic glutamate release and greater depolarization of the post-synaptic neurons, opening the Ca2+ channels of the NMDA receptors (Cooke & Bliss, 2006). The strengthening of the synaptic connections result from the insertion of novel AMPA receptors (Lu et al., 2001).
The positive allosteric modulation of GABAA receptors mRNA in immature hippocampal rat neurons by midazolam affects receptor expression and induces apoptosis
Published in International Journal of Neuroscience, 2019
Barbara Sinner, Julia Steiner, Manuela Malsy, Bernhard M. Graf, Anika Bundscherer
In the early period of brain development, glutamatergic synaptic transmission is purely NMDA-receptor based and lacks functional AMPA receptors. NMDA receptors are characterized by a higher affinity to glutamate than AMPA receptors. During the later stages of brain maturation glutamatergic transmission is also facilitated via AMPA receptors. These are assemblies consisting of four subunits GluA1–4 [8]. AMPA receptors undergo typical subunit changes during brain maturation. Early in development many synapses contain GluA2-lacking, Ca2+-permeable AMPA receptors, which are exchanged for GluA2-containing AMPA receptors after the second postnatal week. The predominant expression of GluA1 is highly developmental restricted and in 14 days old rats AMPA receptors mainly consist of GluA2 subunits [9]. Therefore, we evaluated the effect of benzodiazepine administration on GluA1 and A2 receptor expression.