B02 Early defects in a mouse model of HD

Background Motor symptoms linked to Huntington’s disease (HD) are preceded by a progressive decline of cognitive function, psychiatric disturbances or sleep/wake cycle alteration. HD progression and symptoms are recapitulated in transgenic mouse models such as the R6/1 mouse line because of adult onset, slow disease progression and early cognitive deficits beginning at 3 months of age. Aims and Methods To assess the extent of early alterations in HD we used molecular (Western blots, immunohistochemistry, high resolution microscopy), functional (electrophysiology) and behavioral analyses (video tracking). Results Significant changes of neuronal activity in addition to disorganization of functional brain networks in vivo were found in our HD mice at early ages at which no overt behavioral phenotypes are observed. We also found early alterations of inhibitory neurotransmission in the brain of R6/1 mice. Interestingly, these early alterations were concomitant with significant changes of sleep-wake rhythm. Conclusions The long-term stability and function of brain physiology is dependent on proper neuronal functional connections and on an accurate synaptic transmission. Therefore, our data suggest that alterations of neuronal networks and of neurotransmission may be instrumental in the early pathology of the disease. Together with early sleep disturbance, at the very least, they may contribute to HD symptoms. Alterations arising at this young age may provide useful information for the identification of early biomarker as well as new therapeutic approaches aimed at delaying the disease onset.