The significance for CNS function of glutamate-gated cation channels that exhibit high-affinity kainate sites is not understood. Such receptors, which on dorsal root ganglia and in recombinant systems exhibit currents that rapidly desensitize to kainate application, have not been detected electrophysiologically in the brain. However, a comparison of the distribution of mRNAs encoding five glutamate receptor subunits exhibiting high-affinity kainate sites (GluR-5-GluR- 7, KA-1, and KA-2) indicates that high-affinity kainate receptors are most likely involved in all central neuronal circuits of the rat brain. The KA-1 mRNA occurs mainly in the CA3 field of the hippocampus and dentate gyrus, with much lower amounts being found in inner cortical layers, cerebellar Purkinje cells, and white matter (e.g., corpus callosum and anterior commissure). The KA-2 gene is widely expressed in many neuronal nuclei including layers II-VI of neocortex, hippocampal pyramidal (CA1-CA3) and dentate granule cells, septal nuclei such as the bed nucleus of the stria terminalis, medial preoptic, suprachiasmatic, and ventral medial hypothalamic nuclei, dorsal raphe, locus coeruleus, and cerebellar granule cells. KA-2 mRNA is also found in the pineal gland. GluR-5 transcripts are in the cingulate and piriform cortex, the subiculum, lateral septal nuclei, anteroventral thalamus, suprachiasmatic nucleus, the tegmental nuclei, pontine nuclei, and Purkinje cells. GluR-6 mRNA is most abundant in cerebellar granule cells, with lower levels in caudate-putamen and the pyramidal cell layers and dentate granule cells of hippocampus. The GluR-7 gene is prominently expressed in the inner neocortical layers and some cells in layer II, subiculum, caudate-putamen, reticular thalamus, ventral medial hypothalamic nucleus, pontine nuclei, and in putative stellate/basket cells in the cerebellum. These findings suggest that a complex mosaic of receptor variants underlies the high-affinity kainate receptor in the vertebrate brain.