Subtle Alterations in Glutamatergic Synapses Underlie the Aging-Related Decline in Hippocampal Function
David R. Riddle in Brain Aging, 2007
Based on the functional significance of glutamate receptor subunits, it is likely that declines in NMDA and AMPA receptor subunits are associated with impaired synaptic plasticity. For example, as both NMDA and AMPA receptor subunits are essential for LTP induction and maintenance [86, 88, 99, 100], the aging-related loss and/or functional impairment of glutamate receptors can contribute to the LTP deficits in the brains of aged animals [14,101–105]. Declines in NMDA and AMPA receptors each induce cellular changes. Specifically, the aging-related decrease of functional NMDA receptors in rats has been shown to lead to impaired synaptic transmission and LTP induction, and thus to compromised synaptic plasticity [76, 78, 88, 89, 96, 97]. As AMPA receptors mediate most of the fast excitatory synaptic transmission and their number is the major determinant of synaptic efficacy [85], an aging-related loss of these receptors is also associated with impaired synaptic transmission and compromised synaptic plasticity [106]. Moreover, a diminished expression of AMPA receptors in both perforated and nonperforated synapses may have a deleterious effect on cognitive function, even when the synapse number is constant [38]. Without AMPA receptors, glutamatergic synapses in hippocampus are functionally silent. Thus, a loss of AMPA receptors may transform functional synapses into silent ones during aging and contribute to aging-related cognitive impairment [48, 49].
Neurotransmitters and pharmacology
Mark J. Ashley, David A. Hovda in Traumatic Brain Injury, 2017
Several glutamate receptor antagonists are available for experimental work in animals, and some of these have been described previously for both the AMPA and NMDA receptors. There are only two clinically used drugs that have NMDA antagonist properties that are believed to contribute to their therapeutic effects or side effects in a significant way. These include memantine (Namenda®) and ketamine. However, there are other drugs on the market that have minor glutamate receptor antagonistic action (e.g., felbamate and amantadine) along with other effects. Glutamate receptor antagonists are of interest for treating such disorders as epilepsy, ischemic stroke, and posttraumatic brain injury. Moreover, such drugs are believed to have some potential in various neurodegenerative diseases, such as Huntington’s chorea, Alzheimer’s disease, Fredrick’s ataxia, and others. Indeed, memantine is used to treat Alzheimer’s disease. Thus, the search for new glutamate receptor blockers continues to be active research. One disappointing aspect of this work has been psychotic-like side effects that have accompanied the testing of some NMDA antagonists in humans.
Mesolimbic Interactions with Mesopontine Modulation of Locomotion
Peter W. Kalivas, Charles D. Barnes in Limbic Motor Circuits and Neuropsychiatry, 2019
Additional studies concerning modulation of DA in the NAc have found that bilateral injections of cholecystokinin significantly attenuated the supersensitive locomotor response to apomorphine.41 Glutamate receptors also appear to be involved in this modulation. Injection of the glutamate antagonist L-glutamic diethyl ester into the NAc reduced the locomotor-activating effect of amphetamine and cocaine.42 Furthermore, injections of the glutamatergic agonists NMDA and AMPA into the NAc increased locomotor activity when DA fibers were intact, but not following 6-OHDA damage of these fibers.43This result suggests that glutamate receptors are located on DA terminals in the NAc.
Clinical effects and outcomes of perampanel overdoses reported to U.S. poison centers
Published in Clinical Toxicology, 2022
Faisal Syed Minhaj, James B. Leonard, Wendy Klein-Schwartz
Perampanel is a newer antiepileptic agent that was approved in the United States in 2012 for use in adults with partial onset seizures [1]. The mechanism of action for perampanel is unique among antiepileptic agents as it inhibits glutamate activity on AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Glutamate is the primary excitatory neurotransmitter in the central nervous system acting on AMPA glutamate receptors. Perampanel is thought to antagonize this receptor and decrease the overstimulation that can occur with seizure activity, leading to decreased signal transmission. Currently, there are few published case reports describing acute overdose [2–5]. Reported symptoms include prolonged central nervous system depression, respiratory depression, and aggressive behavior requiring chemical and physical restraints. Recently, approval was expanded for more seizure disorders and for use in the pediatric population, potentially increasing availability.
Spider toxins targeting ligand-gated ion channels
Published in Toxin Reviews, 2021
Olena Filchakova
Glutamate receptors have a tetrameric structure with ligand-binding sites for the endogenous ligand, glutamate. The diversity of the receptors is due to multiple receptor subunits that can assemble into different functional receptor subtypes with distinct pharmacological properties (Traynelis et al. 2010, Kumar and Mayer 2013). Each subunit has extracellular amino-terminal and ligand-binding domains (ATD and LBD, respectively), a transmembrane domain (TMD), and an intracellular carboxy-terminal domain (CTD). The transmembrane domain is composed of four membrane loops (M1–M4) with M2 contributing to the selectivity filter. M1, M3, and M4 are membrane-spanning α helices, while M2 is a short membrane segment with N-terminal α helix and C-terminal loop (Sobolevsky et al. 2009). Figure 1 shows the structure of the homotetrameric AMPA receptor composed of GluA2 subunits, as a representative example of a glutamate receptor.
Location of neonatal microglia drives small extracellular vesicles content and biological functions in vitro
Published in Journal of Extracellular Vesicles, 2020
Adriana-Natalia Murgoci, Marie Duhamel, Antonella Raffo-Romero, Khalil Mallah, Soulaimane Aboulouard, Christophe Lefebvre, Firas Kobeissy, Isabelle Fournier, Monika Zilkova, Denisa Maderova, Milan Cizek, Dasa Cizkova, Michel Salzet
To better understand the proteome modulation between cortex and SpC-M and the impact of LPS treatment, ANOVA tests were performed with non-supervised clustering of samples. Two main clusters were highlighted. The first cluster represented overexpressed proteins in both cortex and spinal cord after LPS stimulation, while the second cluster represented overexpressed proteins only in Cx-M cells (Figure 2(d) and Table 2). A single protein was detected to be overexpressed solely in spinal cord under basal conditions: the UPF0183 protein C16orf70 homolog. It is reported to bind to the glutamate receptor. Pathways for each cluster have been analysed using pathway Studio for systems biology analyse (Figure 2(d(ii, iii)) and Table 3). Cluster 1 is enriched in proteins involved in inflammation and the adaptive immune response (Figure 2(d(ii)) whereas, cluster 2 contains proteins related to neuroblastoma and cancer (Figure 2(d(iii))). All these proteins are under-expressed in SpC-M. We focused our interest on the proteins involved in inflammation and neurogenesis (Table 4).