Abstract

We recently reported the existence of medium and large intemeurons immunoreactive for the calcium-binding protein calretinin in the human striatum. We also showed a selective sparing of all medium, but not all large, calretinin-immunoreactive striatal neurons in Huntington's disease striatum. Because glutamate receptor-mediated excitotoxicity has been implicated in the massive loss of striatal projection neurons that characterizes Huntington's disease, we have applied a double-antigen localization procedure to post mortem tissue from eight normal human subjects to determine the expression of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate glutamate receptor subunits 1/2/4 by the calretinin-immunoreactive interneurons. The two types of calretinin-immunoreactive neurons were found to display various patterns of glutamate receptor subunit expression and a specific regionalization was also noted in the expression of these glutamate receptor subunits. Approximately half of the large calretinin-immunoreactive neurons displayed immunoreactivity for glutamate receptor subunits 1 and 2, and about the same proportion of medium calretinin-immunoreactive neurons expressed glutamate receptor subunits 1 and 4. These double-labeled neurons were rather uniformly distributed in the caudate nucleus and putamen. In contrast, as much as 70.1% of the large calretinin-immunoreactive neurons displayed glutamate receptor subunit 4 immunoreactivity in the postcommissural portion of the putamen, an area that corresponds to the sensorimotor striatal territory. For their part, the medium calretinin-immunoreactive neurons were markedly enriched with glutamate receptor subunit 2, 76% of them being double labeled in the caudate nucleus, which corresponds to the striatal associative territory, compared with 85.5% in the postcommissural putamen. Receptor subunit composition plays a key role in determining the functional properties of glutamate receptors, including their permeability to calcium and susceptibility to excitotoxic insults. Thus, the differential expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate glutamate receptor subunits reported here may help to explain the selective sparing of certain types of calretinin-immunoreactive striatal interneurons in Huntington's disease, although other factors, such as post-transcriptional editing, are also likely to be involved.