Abstracts

RATIONALE: Synaptic abnormalities of human cortical dysplasia and intractable seizures result from genetic or prenatal brain damage. We have studied NMDA receptors in specimens from resected dysplastic cortex. We now know that glutamatergic neurons have significant increases in NMDA protein complexes which act throughout the long transmembrane loops to generate seizures. We have used fetal radiated rats to test mechanisms for the development of these hyperexcitable NMDA ion channels that cause focal cortical seizures in both children and adults.
METHODS: Rats were radiated at E17 at 150 Rads and studied at birth (PN0), PN7, and later dates using membrane co-immunoprecipitation of NR1-NR2B.
RESULTS: By the use of co-immunoprecipitation we have found the developmental period in which the NMDA subunits first appear in normal rat cortex. The NR1 subunit is not expressed until E16, while the NR2B subunit is expressed as early as E14. However, these two NMDA receptor subunits are not physically coassembled until birth (PN0). In radiated rats, there was no detectable difference in NR1/NR2B expression at birth. However, at one week (PN7), development of the NR1-NR2B coassemblies were more than double that of the normal rats.
CONCLUSIONS: With the well-controlled studies in radiated fetal rats we can quantify the [dsquote]critical periods[dsquote] when the glutamate NMDA receptor subunits develop anomalous permanent physical coassemblies. The NR1-NR2B protein sequences could result in hyperexcitability even during normal levels of glutamate transmitter release. The many possible changes in the NMDA receptor proteins may uncover unique physiochemical subunit interactions in receptor membranes and in selective mRNA expressions. This may aid in designing new therapeutic agents targeted for block of the epileptogenesis without significantly altering normal neuron excitability.
Support: Supported by NIH Grants NS 31655 and 38150 (T.L.B.).