Abstract
The classical clinical symptoms of Huntington’s disease (HD) include abnormal involuntary movements (chorea) and cognitive impairment. This genetically determined disorder selectively involves degeneration of striatal spiny neurons while sparing striatal large cholinergic interneurons.1 HD is caused by an expansion of CAG repeats near the 5′ end of the IT15 gene. IT15 encodes an ubiquitously expressed protein called huntingtin. Moreover, a remarkable decrease in the activity of mitochondrial complex II (succinate dehydrogenase, SD) has been found in brains of HD patients.2 Indeed, the link between bioenergetic defects and excitotoxic mechanisms, two pathological events which seems to play a major role in HD3,4 to the mutated huntingtin, remains unknown. The corticostriatal projection represents one of the major glutamatergic pathways in the brain and an abnormal release of glutamate from this pathway seems to play a pathogenic role in HD. The complex II inhibitors 3-nitropropionic acid (3-NP) and methylmalonic acid (MMA) mimic the pathology of HD.5,6 Thus, enhanced glutamatergic transmission may trigger neurodegeneration in neurons, the energy metabolism of which is compromised due to impaired SD activity. We studied the electrophysiological effects of the pharmacological blockade of SD by either 3-NP or MMA on glutamatergic excitatory postsynaptic potentials (EPSPs), in order to investigate the link between metabolism impairment and glutamatergic transmission both in striatal spiny neurons and cholinergic interneurons. The t-LTP might play a key role in the regional and cell-type specific neuronal death observed in HD.
Published Version
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