NMDA receptor composition differs among anatomically diverse malformations of cortical development

Altered excitatory synaptic activity is likely a key factor in the neuronal hyperexcitability of developmental cerebral malformations. Using a combined morphologic and molecular approach, we investigated the NMDA receptor and related protein composition in human epileptic patients affected by periventricular nodular heterotopia, subcortical band beterotopia, or focal cortical dysplasia. Our results indicate that expression levels of specific NMDA receptor subunits are altered in both cerebral heterotopia and cortical dysplasia. A selective increase in the NR2B subunit was present in all cortical dysplasia, whereas the expression level of NR2A and NR2B subunits was significantly downregulated in all patients with heterotopia. NR2B upregulation in cortical dysplasia was greater in the total homogenate than the postsynaptic membrane fraction, suggesting that mechanisms other than increased ionic influx through the postsynaptic membrane may sustain hyperexcitability in dysplastic neurons. In cerebral heterotopia, the NR2A and NR2B downregulation was accompanied by less evident reduction of the SAP97 and PSD-95 proteins of the MAGUK family, thus suggesting that NMDA impairment was associated with altered molecular structure of the postsynaptic membrane. Our results demonstrate that diverse human developmental malformations are associated with different alterations of the NMDA receptor, which may contribute to the genesis of epileptic phenomena.