Loss of cortical and thalamic neuronal tenascin-C expression in a transgenic mouse expressing exon 1 of the human Huntington disease gene

A transgenic mouse containing the first exon of the human Huntington's dise ase (HD) gene has revealed a variety of behavioral and pathophysiological a nomalies reminiscent of certain aspects of human Huntington's disease (HD). The present study has found that expression of the extracellular matrix gl ycoprotein tenascin-C appears to be unaffected in astroglial cells in wild- type and R6/2 transgenic mice that express the mutant huntingtin protein bu t that it is conspicuously absent in two neuronal populations within the ce rebral cortex and thalamus of the R6/2 mice. Loss of tenascin-C expression begins between the fourth and eighth postnatal weeks, coincidental with the onset of abnormal behavioral phenotype and the appearance of intranuclear inclusion bodies and neuropil aggregates. By 12 weeks, R6/2 mice exhibit a complete absence of tenascin-C neuronal immunolabeling, a disappearance of cRNA probe-positive neurons across discrete cytoarchitectonic regions of th e dorsal thalamus (e.g., the ventromedial, parafascicular, lateral posterio r, and posterior thalamic groups) and frontal cortex, and an accompanying t halamic astrogliosis. The loss of neuronal tenascin-C expression includes s tructures that are known to send converging excitatory axonal projections t o the caudate-putamen, the structure that is most at risk for neurodegenera tion in HD. Altered neuronal expression of tenascin-C in R6/2 mice implicat es altered transcriptional activities of the mutant huntingtin protein. The abnormal biochemistry and possibly abnormal activity of thalamostriate and corticostriate projection neurons may also affect abnormal neuronal activi ties in their primary connectional target, the neostriatum, which is severe ly compromised in HD. (C) 2001 Wiley-Liss, Inc.