Mechanical injury modulates AMPA receptor kinetics via an NMDA receptor-dependent pathway.
Alterations in glutamatergic transmission are thought to contribute to secondary neuronal damage following traumatic brain injury. Using an in vitro cell injury model, we previously demonstrated an apparent reduction in AMPA receptor desensitization and resultant potentiation of AMPA-evoked currents after stretch injury of cultured neonatal rat cortical neurons. In the present study, we sought to further characterize injury-induced enhancement of AMPA current and elucidate the mechanisms responsible for this pathological process. Using the patch-clamp technique, agonist-activated currents were recorded from control and injured neurons. Potentiation of AMPA-mediated currents occurred quickly, within 15-30 min following injury, and persisted for at least 24 h. Stretch-injury slowed the activation and desensitization of AMPA mediated currents recorded from excised outside-out patches. The co-application of 100 microM AMPA and 20 microM thiocyanate enhanced AMPA receptor desensitization in control neurons and restored desensitization in injured neurons. The potentiation of AMPA-elicited current was prevented by the NMDA receptor antagonist D-APV (20 microM) or the CaMKII inhibitor KN93 (10 microM). These results suggest that mechanical injury initiates a biochemical cascade that involves NMDA receptor and CaMKII activation and produces a long-lasting reduction of AMPA receptor desensitization, which may contribute to the pathophysiology of traumatic brain injury.
Goforth
Paulette B
PB
Department of Pharmacology and Toxicology, Virginia Commonwealth University Medical Center, Richmond, Virginia 23298, USA.
Ellis
Earl F
EF
Satin
Leslie S
LS
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000494:pharmacology; D018929:Cell Culture Techniques; D007700:Kinetics; D040542:Mechanotransduction, Cellular / Q000187:drug effects / Q000502:physiology*; D009457:Neuroglia / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013314:Stress, Mechanical; D013861:Thiocyanates / Q000494:pharmacology; D013997:Time Factors
D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D013861:Thiocyanates; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C031760:thiocyanate