Early alterations in gene expression and cell morphology in a mouse model of Huntington's disease

Several mouse models for Huntington's disease (HD) have been produced to da te. Based on differences in strain, promoter, construct, and number of glut amines, these models have provided a broad spectrum of neurological symptom s, ranging from simple increases in aggressiveness with no signs of neuropa thology, to tremors and seizures in absence of degeneration, to neurologica l symptoms in the presence of gliosis and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling) positivity, and finally to sel ective striatal damage associated with electrophysiological and behavioral abnormalities. We decided to analyze the morphology of striatum and hippoca mpus from a mouse transgenic line obtained by microinjection of exon 1 from the HD gene after introduction of a very high number of CAG repeat units. We found a massive darkening and compacting of striatal and hippocampal neu rons in affected mice, associated with a lower degree of more classical apo ptotic cell condensation. We then explored whether this morphology could be explained with alterations in gene expression by hybridizing normal and af fected total brain RNA to a panel of 588 known mouse cDNAs. We show that so me genes are significantly and consistently up-regulated and that others ar e down-regulated in the affected brains. Here we discuss the possible signi ficance of these alterations in neuronal morphology and gene expression.