Abstracts

Rationale: Roper and colleagues have reported that rats given gamma radiation in utero will at adulthood develop diffuse cortical dysplasias, altered glial distributions, and increased seizure propensities. We adopted this rat model of cortical dysplasia and discovered that the dysplastic cortical neurons had the same types of increases in NR1-NR2 coassembly in NMDA receptors that we routinely find in resected human epileptic cortical dysplasias. This rat model represents the possibility of testing the development of molecular mechanisms controlling the permanent NR1-NR2 coassemblies responsible for NMDA receptor increased conductances. Methods: Rats were radiated at E17 at 150 Rads and studied at birth ( PN0), PN7, and later dates using membrane coprecipitation of NR1-NR2A/B, and mRNA using Northerns and RT-PCR. Results: In all normal rats at PN0, the rank order of increasing mRNA expressions were NR2B>NR1-N1>NR1-C1>NR2A, but in normal adults the ranks were NR1-N1>NR2B>NR2A>NR1-C1. The mRNA development in rats shows age changes that may allow NR1-NR2 permanent coassemblies and hyperexcitability of the adult NMDA receptors. By contrast, at birth, the highly expressed NR2B subunit would only be functional if assembled with an NR1 subunit. Using membrane coprecipitation, we found that at birth radiated rats had less NR1-NR2A/B coassembly than normal newborns. At PN7, both radiated and normals had increased NR1-NR2A/B coprecipitation; however, the radiated rats had upregulated NMDA receptors three times greater than the normals. Discussion: These results indicate that seizure susceptibility in the gamma radiated rat may be low but within one week may be very high. This "critical period" or "delay in NMDA receptor development" needs further study. Supported by NIH-NS38150,(T.L.B.).