Down-regulation of AMPA receptors and long-term potentiation during early epileptogenesis.

Published on Nov 1, 2021in Epilepsy & Behavior2.937
· DOI :10.1016/J.YEBEH.2021.108320
Yasmin Cruz Del Angel6
Estimated H-index: 6
(University of Colorado Denver),
James E. Orfila11
Estimated H-index: 11
(Anschutz Medical Campus)
+ 2 AuthorsMarco I. González19
Estimated H-index: 19
(Anschutz Medical Campus)
Sources
Abstract
Abstract null null Epilepsy is a brain disorder characterized by the occurrence of recurrent spontaneous seizures. Behavioral disorders and altered cognition are frequent comorbidities affecting the quality of life of people with epilepsy. These impairments are undoubtedly multifactorial and the specific mechanisms underlying these comorbidities are largely unknown. Long-lasting alterations in synaptic strength due to changes in expression, phosphorylation, or function of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) have been associated with alterations in neuronal synaptic plasticity. In particular, alterations in hippocampal long-term potentiation (LTP), a well-accepted model of learning and memory, have been associated with altered cognition in epilepsy. Here, we analyzed the effects of pilocarpine-induced status epilepticus (SE) on AMPARs to determine if alterations in AMPAR signaling might be one of the mechanisms contributing to altered cognition during epilepsy. We found alterations in the phosphorylation and plasma membrane expression of AMPARs. In addition, we detected altered expression of GRIP, a key scaffolding protein involved in the proper distribution of AMPARs at the neuronal cell surface. Interestingly, a functional analysis revealed that these molecular changes are linked to impaired LTP. Together, these observations suggest that seizure-induced alterations in the molecular machinery regulating AMPARs likely impact the neuron’s ability to support synaptic plasticity that is required for learning and memory.
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ABSTRACT Status epilepticus (SE) is a medical emergency with continuous seizure activity that causes profound neuronal damage, morbidity, or death. SE incidents can arise spontaneously, but mostly are elicited by seizurogenic triggers. Chemoconvulsants such as the muscarinic agonist pilocarpine and organophosphates (OP), such as the pesticide diisopropylfluorophosphate (DFP) and the nerve agent soman, can induce SE. Pilocarpine, DFP, and soman share a common feature of cholinergic crisis that tr...
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Abstract The pilocarpine animal model of status epilepticus is a well-established, clinically translatable model that satisfies all of the criteria essential for an animal model of status epilepticus: a latency period followed by spontaneous recurrent seizures, replication of behavioural, electrographic, metabolic, and neuropathological changes, as well as, pharmacoresistance to anti-epileptic drugs similar to that observed in human status epilepticus. However, this model is also characterized b...
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Hippocampal injury and cognitive impairments are common after cardiac arrest and stroke and do not have an effective intervention despite much effort. Therefore, we developed a new approach aimed at reversing synaptic dysfunction by targeting TRPM2 channels. Cardiac arrest/cardiopulmonary resuscitation (CA/CPR) in mice was used to investigate cognitive deficits and the role of the calcium-permeable ion channel transient receptor potential-M2 (TRPM2) in ischemia-induced synaptic dysfunction. Our ...
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Abstract The initiation and maintenance phases of cholinergic status epilepticus (SE) are associated with maladaptive trafficking of synaptic GABAA and glutamate receptors. The resulting pharmacoresistance reflects a decrease in synaptic GABAA receptors and increase in NMDA and AMPA receptors, which tilt the balance between inhibition and excitation in favor of the latter. If these changes are important to the pathophysiology of SE, both should be treated, and blocking their consequences should ...
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OBJECTIVE: Generalized convulsive status epilepticus is associated with high mortality. We tested whether alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor plasticity plays a role in sustaining seizures, seizure generalization, and mortality observed during focal onset status epilepticus. We also determined whether modified AMPA receptors generated during status epilepticus could be targeted with a drug. METHODS: Electrically induced status epilepticus was characterized by...
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Abstract This review summarizes the efforts of our laboratories to develop a mechanism-based therapy for the treatment of organophosphate (OP) nerve agent-induced seizures. Organophosphate poisoning can occur during warfare and terrorist attacks and in the civilian sphere because of intentional or unintentional poisoning. Persons exposed to OPs experience seizures. We developed animal models of OP poisoning and then evaluated the effects of OP on excitatory α-amino-3-hydroxy-5-methyl-4-isoxazole...
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To correctly transfer information, neuronal networks need to continuously adjust their synaptic strength to extrinsic stimuli. This ability, termed synaptic plasticity, is at the heart of their function and is, thus, tightly regulated. In glutamatergic neurons, synaptic strength is controlled by the number and function of AMPA receptors at the postsynapse, which mediate most of the fast excitatory transmission in the central nervous system. Their trafficking to, at, and from the synapse, is, the...
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#1Saltuk Bugra Baltaci (Selçuk University)H-Index: 6
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LTP is the most intensively studied cellular model of the memory and generally divided at least two distinct phases as early and late. E-LTP requires activation of CaMKII that initiates biochemical events and trafficking of proteins, which eventually potentiate synaptic transmission, and is independent of de novo protein synthesis. In contrast, L-LTP requires gene expression and local protein synthesis regulated via TrkB receptor- and functional prions CPEB2-3-mediated translation. Maintenance o...
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#2Paulina Kazmierska-Grebowska (University of Łódź)H-Index: 2
Last. Benoit Lechat (Katholieke Universiteit Leuven)H-Index: 12
view all 20 authors...
Abstract Background Glycogen synthase kinase-3β (GSK3β) is a key regulator of cellular homeostasis. In neurons, GSK3β contributes to the control of neuronal transmission and plasticity, but its role in epilepsy remains to be defined. Methods Biochemical and electrophysiological methods were used to assess the role of GSK3β in regulating neuronal transmission and epileptogenesis. GSK3β activity was increased genetically in GSK3β[S9A] mice. Its effects on neuronal transmission and epileptogenesis ...
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The regulation of synaptic AMPA receptors (AMPARs) is critical for excitatory synaptic transmission, synaptic plasticity and the consequent formation of neural circuits during brain development and their modification during learning and memory processes. The number of synaptic AMPARs is regulated through endocytosis, exocytosis and endosomal sorting that results in recycling back to the plasma membrane or degradation in the lysosome. Hence, endo-lysosomal sorting is vitally important in maintain...
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