Enhanced sensitivity to N-methyl-D-aspartate receptor activation in transgenic and knockin mouse models of Huntington's disease

We used two mouse models of Huntington's disease (HD) to examine changes in glutamate receptor sensitivity and striatal electrophysiology. One model, a transgenic, consisted of mice expressing exon 1 of the human HD gene and carrying 141-157 CAG repeat sequences (R6/2 line). The second model, a CAG repeat "knockin," consisted of mice with different lengths of CAG repeats ( CAG71 and CAG94 repeats). The effects of glutamate receptor activation were examined by visualizing neurons in brain slices with infrared videomicrosc opy and differential interference contrast optics to determine changes in s omatic area (cell swelling). Striatal and cortical neurons in both models ( R6/2 and CAG94) displayed more rapid and increased swelling to N-methyl-D-a spartate (NMDA) than those in controls, This effect was specific as there w ere no consistent group differences after exposure to alpha-amino-3-hydroxy -5-methyl-4-isoxazole propionic acid (AMPA) or kainate (KA). Intracellular recordings revealed that resting membrane potentials (RMPs) in the R6/2 tra nsgenics were significantly more depolarized than those in their respective controls. RMPs in CAG94 mice also were more depolarized than those in CAG7 1 mice or their controls in a subset of striatal neurons. Confirming previo us results, R6/2 mice expressed behavioral abnormalities and nuclear inclus ions. However, CAG71 and CAG94 knockins did not, suggesting that increased sensitivity to NMDA may occur early in the disease process. These findings imply that NMDA antagonists or compounds that alter sensitivity of NMDA rec eptors may be useful in the treatment of HD, J. Neurosci. Res. 58:515-532, 1999. (C) 1999 Wiley-Liss, Inc.