Workshop 6

Huntington’s disease (HD) is caused by a CAG trinucleotide repeat expansion encoding a polyglutamine tract in the huntingtin protein. HD patients exhibit cognitive deficits (culminating in dementia), psychiatric symptoms (the most common of which is depression) and motor abnormalities (e.g., chorea). In a transgenic mouse model of HD we have correlated early deficits of synaptic plasticity and hippocampal neurogenesis with onset of cognitive and affective abnormalities, and identified potential molecular mechanisms mediating this pathological plasticity . We have also demonstrated that altered sensory, cognitive and motor stimulation can dramatically modify the disease process in HD mice. A more specific component of environmental enrichment, voluntary physical exercise, was found to delay the onset of hippocampal-dependent behavioural deficits. Our findings indicate that the modulatory effects of various environmental stimuli are mediated by experiencedependent changes in transcription of specific genes implicated in adult neurogenesis and synaptic plasticity. Transcription of various genes, including brain-derived neurotrophic factor (BDNF) and serotonin receptors (5-HTRs), is disrupted by the HD mutation at an early stage in both the hippocampus and neocortex, associated with onset of the cognitive and affective signs. These findings have been extended by our group, and others, to a variety of different rodent models of neurodegenerative diseases. We have shown that environmental enrichment has sex-specific modulatory effects in a SOD1 transgenic mouse model of amyotrophic lateral sclerosis, which differ significantly from voluntary physical exercise alone, via accessing to running wheels. These findings indicate that both the quantity and quality of enhanced mental and physical exercise are important, and may inform novel therapeutic approaches (including a proposed class of drugs called enviromimetics ) for a range of different neurodegenerative diseases.