MECHANISMS UNDERLYING CELL-TYPE SPECIFIC VULNERABILITY OF STRIATAL NEURONS: IMPLICATIONS FOR HUNTINGTON’S DISEASE

Huntington’s disease (HD) is a genetic degenerative disorder causing chorea, dementia and premature death. The HD gene is located on the short arm of chromosome 4. Symptoms of HD are due to the death of striatal GABAergic spiny neurons, while striatal cholinergic interneurons are spared. Excitotoxicity and energy metabolism failure contribute to cell death in the HD striatum. Accordingly, HD patients have reduced striatal mitochondrial complex II activity and we are recently shown that inhibitors of mitochondrial complex II cause abnormal excitatory synaptic plasticity. The aim of the present project is to further investigate the interaction between abnormal excitatory transmission and energy metabolism failure in different experimental model. i) acute application of various inhibitors of specific mitochondrial enzymes in corticostriatal slice preparations obtained from normal rats, ii) slices obtained from rats chronically intoxicated with 3-NP, iii) slices obtained from HD transgenic mice (R6/2, R6/1). Synaptic changes following inhibition of mitochondrial complexes and genetic alterations will be investigated. We will also try to design possible neuroprotective strategies targeting some of the biochemical steps involved in the abnormal striatal synaptic circuitry during HD.