We have used RNA in situ hybridization to study the regional expression of the Huntington's disease gene (HD) and its rat homologue in brain and selected nonneural tissues. The HD transcript was expressed throughout the brain in both rat and human, especially in the neurons of the dentate gyrus and pyramidal neurons of the hippocampal formation, cerebellar granule cell layer, cerebellar Purkinje cells and pontine nuclei. Other brain areas expressed lower levels of the HD transcript without pronounced regional differences. Neuronal expression predominated over glial expression in all regions. HD mRNA was also expressed in colon, liver, pancreas and testes. The regional specificity of neuropathology in HD, which is most prominent in the basal ganglia, thus cannot be accounted for by the pattern of expression of HD.

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Excitatory amino acids (EAA) such as glutamate and aspartate are probably the neurotransmitters of a majority of mammalian neurons. Only a few previous studies have been concerned with the distribution of the subtypes of EAA receptor binding in the primate brain. We examined NMDA- and quisqualate-sensitive [3H]glutamate binding using quantitative autoradiography in monkey brain (Macaca fascicularis). The two types of binding were differentially distributed. NMDA-sensitive binding was most dense in dentate gyrus of hippocampus, stratum pyramidale of hippocampus, and outer layers of cerebral cortex. Quisqualate-sensitive binding was most dense in dentate gyrus of hippocampus, inner and outer layers of cerebral cortex, and molecular layer of cerebellum. In caudate nucleus and putamen, quisqualate- and NMDA-sensitive binding sites were nearly equal in density. However, in globus pallidus, substantia nigra, and subthalamic nucleus, quisqualate-sensitive binding was several-fold greater than NMDA-sensitive binding. In thalamus, [3H]glutamate binding was generally low for both subtypes of binding except for the anterior ventral, lateral dorsal, and pulvinar nuclei. In the brainstem, low levels of binding were found, and strikingly the red nucleus and pons, which are thought to receive glutamatergic projections, had approximately 1/20 the binding observed in cerebral cortex. These results demonstrate that NMDA- and quisqualate-sensitive [3H]glutamate binding are observed in all regions of primate brain, but that in some regions one subtype predominates over the other. In addition, certain areas thought to receive glutamatergic projections have low levels of both types of binding.

The excitotoxic hypothesis of Huntington's disease pathogenesis suggests that selective striatal neuronal loss results from excessive activation of striatal excitatory amino acid receptors. Using a microdialysis probe mated to an Alzet 2002 mini-osmotic pump three different concentrations of quinolinic acid or vehicle were administered to the striata of rats over a 3-week period. Animals that received a total of 3.3 mumol of quinolinic acid had significant striatal atrophy that could be attributed to two distinct areas of neuronal loss. First, an area of necrosis surrounding the probe was marked by inflammatory infiltrate and a lack of neurons. In the second region, surrounding the necrotic area, there was a significant reduction in nissl-stained cells, with relative sparing of NADPH-diaphorase-staining neurons. In addition, there was a reduction in cytochrome oxidase staining throughout both of the areas of cell loss. Beyond the area of cell loss, the striatum appeared normal in all respects. The striata of animals that received 880 nmol quinolinic acid appeared identical to those that received vehicle. The striata of animals that received 8.8 mumol quinolinic acid showed severe nonselective atrophy of the striatum and some surrounding structures. We conclude that dialytic delivery of 3.3 mumol quinolinic acid produces an area of neuronal destruction that resembles the selective neuronal loss seen in Huntington's disease. This selective neurodegeneration produced by chronic exposure to quinolinic acid simulates more closely the course of Huntington's disease than previously described methods.

A new and convenient myelin stain is described. Paraformaldehyde fixed tissue is serially immersed in a nitroblue tetrazolium solution and then in a diaminobenzidine solution. The result is distinct blue staining of myelinated fiber tracts. This technique has advantages over presently used myelin stains.

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