Differential responses to NMDA receptor activation in rat hippocampal interneurons and pyramidal cells may underlie enhanced pyramidal cell vulnerability.
Hippocampal interneurons are generally more resistant than pyramidal cells to excitotoxic insults. Because NMDA receptors play a crucial role in neurodegeneration, we have compared the response to exogenous NMDA in CA1 pyramidal cells and interneurons of the stratum oriens using combined whole-cell patch-clamp recording and ratiometric Ca2+ imaging. In voltage-clamp, current-clamp or in nominally Mg2+-free medium, NMDA (10 microM; 3-5 min exposure in the presence of tetrodotoxin) induced a markedly larger inward current and Ca2+ rise in pyramidal cells than in interneurons. Pyramidal cells also showed a more pronounced voltage dependence in their response to NMDA. We hypothesized that this enhanced response to NMDA receptor activation in pyramidal cells could underlie their increased vulnerability to excitotoxicity. Using loss of dye as an indicator of degenerative membrane disruption, interneurons tolerated continuous exposure to a high concentration of NMDA (30 microM) for longer periods than pyramidal cells. This acute neurodegeneration in pyramidal cells was independent of intracellular Ca2+, because high intracellular BAPTA (20 mM) did not prolong survival time. Thus, a plausible explanation for the enhanced sensitivity of pyramidal neurons to excitotoxic insults associated with cerebral ischemia is their greater response to NMDA receptor activation, which may reflect differences in NMDA receptor expression and/or subunit composition.
Avignone
E
E
Neurosciences Institute, Division of Pathology & Neuroscience, University of Dundee, Ninewells Hospital, Dundee, UK DD1 9SY. elena.avignone@univ-paris5.fr
Frenguelli
B G
BG
Irving
A J
AJ
D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D002614:Chelating Agents / Q000494:pharmacology; D003952:Diagnostic Imaging / Q000379:methods; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005971:Glutamates / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007395:Interneurons / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D016202:N-Methylaspartate / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D017966:Pyramidal Cells / Q000502:physiology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
D000779:Anesthetics, Local; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D007211:Indoles; C476559:N-methylglutamate; D016194:Receptors, N-Methyl-D-Aspartate; D013779:Tetrodotoxin; D004533:Egtazic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium; C000543:cyclopiazonic acid