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Calcium-Permeable AMPA Receptors Appear in Cortical Neurons after Traumatic Mechanical Injury and Contribute to Neuronal Fate
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Traumatic brain injury (TBI) is one of the most disabling injuries in the population, with 1.5 million Americans new cases each year and 5.3 million Americans overall requiring long-term daily care as a result of their injuries. One critical aspect in developing effective treatments for TBI is determining if new, specific receptor populations emerge in the early phase after injury that can subsequently be targeted to reduce neuronal death after injury. One specific glutamate receptor subtype, the calcium-permeable AMPA receptor (CP-AMPAR), is becoming increasingly recognized for its role in physiological and pathophysiological processes. Although present in relatively low levels in the mature brain, recent studies show that CP-AMPARs can appear following ischemic brain injury or status epilepticus, and the mechanisms that regulate the appearance of these receptors include alterations in transcription, RNA editing, and receptor trafficking. In this report, we use an in vitro model of TBI to show a gradual appearance of CP-AMPARs four hours following injury to cortical neurons. Moreover, the appearance of these receptors is mediated by the phosphorylation of CaMKIIalpha following injury. Selectively blocking CP-AMPARs after mechanical injury leads to a significant reduction in the cell death that occurs 24 h following injury in untreated controls, and is similar in protection offered by broad-spectrum NMDA and AMPA receptor antagonists. These data point to a potentially new and more targeted therapeutic approach for treating TBI.
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“Consistent with the notion that the presence of Ca 2+ -permeable AMPA receptors contributes to the vulnerability of PV-INs, blocking of these receptors attenuates cortical neuron death in an in vitro model of traumatic brain injury; attenuates hippocampal pyramidal neuron loss in a mouse hippocampal slice model of oxygen-glucose deprivation; and attenuates retinal ganglion cells loss in a rat”
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Metadata
- Authors
- Spaethling, J. M., Klein, D. M., Singh, P., & Meaney, D. F.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Meaney, David F.
- Venue
- Journal of Neurotrauma
- Publisher
- SAGE Publications
- Published
- 2008-10
- Volume
- 25
- Issue
- 10
- Pages
- 1207-1216
- ISSN
- 0897-7151 (ISSN-L)
- 1557-9042
- PMC
- PMC2799682
- OpenAlex
- W2096887290
- Cited by
- 112
- References
- 60
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 11 · 2020: 7 · 2019: 4 · 2018: 4 · 2017: 5 · 2016: 6 · 2015: 10 · 2014: 3 · 2013: 6 · 2012: 8
- FWCI
- 5.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neurotrauma (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (NS35712, R01NS035712)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD041699)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury Research
- Keywords
- calcium-permeable AMPA receptors, traumatic brain injury, cortical neurons, neuronal cell death, receptor trafficking, AMPA receptor antagonists, NMDA receptor antagonists, glutamate receptors
- MeSH terms
- Animals, Brain Injuries, Calcium, Cells, Cultured, Cerebral Cortex, Cytosol, Nerve Degeneration, Neurons, Stress, Mechanical, Time Factors, Up-Regulation, Cell Death, RNA Editing, Receptors, AMPA, Patch-Clamp Techniques, Excitatory Amino Acid Antagonists, Neuroprotective Agents, Cytoprotection, Calcium Signaling, Protein Transport, Rats, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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