title: NMDA receptor mediated phosphorylation of GluR1 subunits contributes to the appearance of calcium-permeable AMPA receptors after mechanical stretch injury.
abstract: Alterations in neuronal cytosolic calcium is a key mediator of the traumatic brain injury (TBI) pathobiology, but less is known of the role and source of calcium in shaping early changes in synaptic receptors and neural circuits after TBI. In this study, we examined the calcium source and potential phosphorylation events leading to insertion of calcium-permeable AMPARs (CP-AMPARs) after in vitro traumatic brain injury, a receptor subtype that influences neural circuit dynamics for hours to days following injury. We found that both synaptic and NR2B-containing NMDARs contribute significantly to the calcium influx following stretch injury. Moreover, an early and sustained phosphorylation of the S-831 site of the GluR1 subunit appeared after mechanical injury, and this phosphorylation was blocked with the inhibition of either synaptic NMDARs or NR2B-containing NMDARs. In comparison, mechanical injury led to no significant change in the S-845 phosphorylation of the GluR1 subunit. Although no change in S-845 phosphorylation appeared in injured cultures, we observed that inhibition of NR2B-containing NMDARs significantly increased S-845 phosphorylation 1h after injury while blockade of synaptic NMDARs did not change S-845 phosphorylation at any time point following injury. These findings show that a broad class of NMDARs are activated in parallel and that targeting either subpopulation will reverse some of the consequences of mechanical injury, providing distinct paths to treat the effects of mechanical injury on neural circuits after TBI.
authors.affiliation: Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Spaethling
authors.forename: Linda
authors.initials: L
authors.lastname: Le
authors.forename: David F
authors.initials: DF
authors.lastname: Meaney
mesh_terms: D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D015153:Blotting, Western; D001930:Brain Injuries / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
chemical_list: D001640:Bicuculline; D002118:Calcium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D016291:Dizocilpine Maleate; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D010636:Phenols; D010880:Piperidines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C121001:NR2B NMDA receptor; C109643:Ro 25-6981