Abstract

Huntington's disease (HD) is a neurodegenerative disorder characterized by progressive abnormalities in cognitive and motor control. Several studies have demonstrated an impairment in glucose metabolism in the basal ganglia and in the cerebral cortex of symptomatic HD patients. When HD animal models become behaviourally active, the level of ascorbic acid in striatal extracellular fluid is abnormally low in relation to that of littermate controls. We have demonstrated that intracellular ascorbic acid inhibits glucose transport and stimulates lactate transport in synaptically active neurons. In this work we studied the ability of glucose to support synaptic activity in neuronal cells from HD mice (R6/2 mice). Synaptic activity was measured as recordings from striatal medium-sized spiny neurons, using the whole cell configuration in the voltage-clamp mode. Excitatory postsynaptic currents were evoked by stimulating corticostriatal pathway. Using immunofluoresence, qPCR and Western blot analyses we explored protein and mRNA levels of proteins involved in neuronal metabolism modulation. Ascorbic acid was not able to modulate the ability of glucose to serve as an energetic fuel sustaining glutamatergic synaptic activity in presymptomatic and symptomatic HD animals. The presynaptic component was not affected, suggesting a failure on postsynaptic neuron. Abnormalities observed in the ascorbic acid-dependent modulation of neuronal metabolism of presymptomatic R6/2 mice, suggest that ascorbic acid homeostasis failure could be important in the development of HD.