NMDA Receptor-Dependent Epileptogenicity in the Hippocampi of Calcineurin A? Null Mutant Mice
Abstract number :
E.01
Submission category :
Year :
2000
Submission ID :
1121
Source :
www.aesnet.org
Presentation date :
12/2/2000 12:00:00 AM
Published date :
Dec 1, 2000, 06:00 AM
Authors :
David N Lieberman, Joachim Behr, Nils O Dalby, Istvan Mody, Stanford Univ Sch of Medicine, Stanford, CA; Charite, Berlin, Germany; UCLA Sch of Medicine, Los Angeles, CA.
RATIONALE: In human mesial temporal lobe epilepsy (TLE), and animal models of the disease (e.g., kindling) there is a loss of the negative feedback on NMDA channel openings normally provided by the phosphatase calcineurin (CN). We now report that mice deficient of CN (CN-A? -/-) have increased hippocampal NMDA-receptor function, heightened neuronal excitability and epileptiform activity characteristic of TLE. METHODS:Brain slices were prepared from CN-A? -/- mutants and their wild-type littermates. Cell-attached NMDA channel recordings were obtained in acutely dissociated dentate gyrus granule cells. RESULTS:NMDA channel openings recorded in CN-A? -/- mice (n=13) granule cells were significantly prolonged (151 ? 10%, 292 ? 33% and 258 ? 30% of the values measured in CN-A? +/+ mice for mean open time, burst and cluster durations respectively). In the wild-type NMDA channel activity was enhanced by 10 ?M okadaic acid, but this effect was occluded in CN-A? -/- consistent with the reduction of CN activity being responsible for the augmentation of NMDA function. Population spikes after perforant path stimulation in modified ACSF (4 mM Mg, 4 mM Ca and 50 M picrotoxin) demonstrated D-AP5 sensitive epileptiform bursting not observed in the wild-type. Perforant path-evoked dentate gyrus field EPSPs of CN-A? -/- displayed a slower rise time and prolonged decay compared to CN-A? +/+ indicating the involvement of NMDA receptors in synaptic transmission. When extracellular [K+] was raised from 2.5 to 8.5 mM, CA3 pyramidal neurons exhibited spontaneous epileptic discharges that were >100% longer and more robust than those in wild-type, indicating a heightened hippocampal excitability in the CN-A? -/-. Immunohistochemical analyses of CNA-? -/- mice revealed another biochemical characteristic of TLE: decreased calbindin-D28K levels in dentate granule cells. CONCLUSIONS: Our findings are consistent with a pivotal role of CN in the regulation of hippocampal excitability and epileptogenesis by providing a Ca-dependent negative feedback on NMDA receptor function. The CN-A? -/- mice were kindly provided by W. Zhang and I. L. Weissman of Stanford University.