Abstracts

RATIONALE: Glutamatergic transmission between neurons occurs at chemical synapses. The NMDA receptor 2A/B (NR2) subclass of ionotropic glutamate receptors has been implicated in the epileptogenic mechanisms of human cortical dysplasia. The normal functioning of the NMDA receptors is dependent on its appropriate clustering and anchoring at the postsynaptic synapses. Recently, the postsynaptic density protein PSD-95, a putative ion channel-clustering protein, has been shown to bind to NR2 subunits of the NMDA receptors. We hypothesized that the levels of interaction of NR2B with PSD-95 would be increased in human epileptogenic cortex. METHODS: We used co-immunoprecipitation and immunoblotting procedures to quantify the levels of NR2B/PSD-95 complex in the membrane proteins of brain tissues from 4 patients suffering from medically intractable focal epilepsy associated with pathologically confirmed cortical dysplasia. Based on subdural grid EEG data, resected cortical tissues were grouped into epileptogenic and non-epileptogenic. RESULTS: In all patients, the amounts of immunoprecipitated complexes, which reflect the level of co-assembly of NR2B with PSD-95, were increased in epileptogenic cortex as compared to non-epileptogenic cortex. CONCLUSIONS: These results suggest that increased anchoring of NR2B at postsynaptic synapses is a cellular mechanism that may contribute to the increased hyperexcitability in cortical dysplasias. Further studies on a larger number of patients are underway to confirm these preliminary results.