Resistance to NMDA toxicity correlates with appearance of nuclear inclusions, behavioural deficits and changes in calcium homeostasis in mice transgenic for exon 1 of the huntington gene

Transgenic Huntington's disease (HD) mice, expressing exon 1 of the human H D gene (lines R6/1 and R6/2), are totally resistant to striatal lesions cau sed by the NMDA receptor agonist quinolinic acid (QA). Here we show that th is resistance develops gradually over time in both R6/1 and R6/2 mice, and that it occurred earlier in R6/2 (CAG-155) than in R6/1 (CAG-115) mice. The development of the resistance coincided with the appearance of nuclear inc lusions and with the onset of motor deficits. In the HD mice, hippocampal n eurons were also resistant to QA, especially in the CA1 region. Importantly , there was no change in susceptibility to QA in transgenic mice with a nor mal CAG repeat (CAG-18). R6/1 mice were also resistant to NMDA-, but not to AMPA-induced striatal damage. Interestingly, QA-induced current and calciu m influx in striatal R6/2 neurons were not decreased. However, R6/2 neurons had a better capacity to handle cytoplasmic calcium ([Ca2+](c)) overload f ollowing OA and could avoid [Ca2+](c) deregulation and cell lysis. In addit ion, basal [Ca2+](c) levels were increased five-fold in striatal R6/2 neuro ns. This might cause an adaptation of R6 neurons to excitotoxic stress resu lting in an up-regulation of defense mechanisms, including an increased cap acity to handle [Ca2+](c) overload. However, the increased level of basal [ Ca2+](c) in the HD mice might also disturb intracellular signalling in stri atal neurons and thereby cause neuronal dysfunction and behavioural deficit s.