Altered regulation of N-methyl-D-aspartate (NMDA) receptors in the diabetic rat brain

Diabetes can have adverse effects on CNS function, which may be resultant of altered NMDA receptor expression. In streptozotocin-diabetic rat brains L-[3H]glutamate-labeled NMDA receptors were reduced in several brain regions. The response to diabetes was variable exhibiting a hierarchy in the sensitivity of the brain regions to the diabetes-induced changes. Superficial layers of the parietal and piriform cortex were highly sensitive likely indicating preferential reduction in NR2B subunits.;Using mice with insulin receptor knockouts, we evaluated the density and distribution of NMDA receptors. There was not a change in overall NMDA receptor density in brain insulin receptor knockout mice.;NR2A and NR2B are the most abundant NMDA receptors in the adult cerebral cortex. At high doses of NVP-AAM007 (an NR2A antagonist) we observed a NVP-insensitive binding component in the diabetic brain. At NVP concentrations sufficient to fully inhibit NR2A and NR2B subunit binding, there remained a distinct population of NMDA-sensitive L-[3H]glutamate binding sites in the diabetic brain outer parietal cortex; indicating a downregulation of NMDA receptors in the diabetic cortex, and an upregulation of an anomalous receptor subpopulation in the superficial layers of the cerebral cortex.;We hypothesize that in the diabetic brain there is a hypofunction of NMDA receptor activity associated with the loss of NMDA receptors in the cerebral cortex. Rats were chronically administered the selective NMDA receptor antagonist MK-801 and examined for the presence of the anomalous NMDA receptor and NR2D-containing NMDA receptors. The anomalous receptor subpopulation was not observed, nor did there appear to be an upregulation of NR2D subunits.;We also tested the hypothesis that the reduction in NR2B subunit expression is responsible for the upregulation of the anomalous NMDA receptor subtype. Mice brains with NR2B partially knocked-down (NR2B +/-) were evaluated and compared to wild type (NR2B +/+). The NR2B +/- mice had a significant reduction in L-[3H]glutamate binding to NMDA receptors in the cerebral cortex, confirming that the majority of NMDA receptors in the cortex contain NR2B subunits. Under pharmacological conditions revealing the anomalous receptor in the diabetic brain, showed no evidence of this in NR2B+/-; nor evidence that NR2D subunits were upregulated.