Transgenic Huntington's disease (HD) mice, expressing exon 1 of the human HD gene (lines R6/1 and R6/2), are totally resistant to striatal lesions caused by the NMDA receptor agonist quinolinic acid (QA). Here we show that this 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 inclusions and with the onset of motor deficits. In the HD mice, hippocampal neurons were also resistant to QA, especially in the CA1 region. Importantly, there was no change in susceptibility to QA in transgenic mice with a normal CAG repeat (CAG-18). R6/1 mice were also resistant to NMDA-, but not to AMPA-induced striatal damage. Interestingly, QA-induced current and calcium influx in striatal R6/2 neurons were not decreased. However, R6/2 neurons had a better capacity to handle cytoplasmic calcium ([Ca2+]c) overload following QA and could avoid [Ca2+]c deregulation and cell lysis. In addition, basal [Ca2+]c levels were increased five-fold in striatal R6/2 neurons. This might cause an adaptation of R6 neurons to excitotoxic stress resulting in an up-regulation of defense mechanisms, including an increased capacity to handle [Ca2+]c overload. However, the increased level of basal [Ca2+]c in the HD mice might also disturb intracellular signalling in striatal neurons and thereby cause neuronal dysfunction and behavioural deficits.

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Neuregulin 1 (NRG1) is a trophic factor that has an essential role in the nervous system by modulating neurodevelopment, neurotransmission and synaptic plasticity. Despite the evidence that NRG1 and its receptors, ErbB tyrosine kinases, are expressed in mesencephalic dopaminergic nuclei and their functional alterations are reported in schizophrenia and Parkinson's disease, the role of NRG1/ErbB signalling in dopaminergic neurons remains unclear. Here we found that NRG1 selectively increases the metabotropic glutamate receptor 1 (mGluR1)-activated currents by inducing synthesis and trafficking to membrane of functional receptors and stimulates phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin (PI3K-Akt-mTOR) pathway, which is required for mGluR1 function. Notably, an endogenous NRG1/ErbB tone is necessary to maintain mGluR1 function, by preserving its surface membrane expression in dopaminergic neurons. Consequently, it enables striatal mGluR1-induced dopamine outflow in in vivo conditions. Our results identify a novel role of NRG1 in the dopaminergic neurons, whose functional alteration might contribute to devastating diseases, such as schizophrenia and Parkinson's disease.

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