Fourth International Symposium on Neuroacanthocytosis

Abstracts from the Fourth International Symposium on Neuroacanthocytosis

July 1-2, 2008
London and Oxford

Chairs: Prof. Kailash Bhatia, MD, FRCP, Institute of Neurology, University College London; Prof. Anthony P. Monaco, MD, PhD, Wellcome Trust Centre for Human Genetics, University of Oxford

Organizers: Antonio Velayos-Baeza, PhD; Susanne Schneider, MD; Glenn Irvine

7-3 Molecular mediators and environmental modulators of corticostriatal neurodegeneration leading to motor, cognitive and psychiatric symptoms: Insights from Huntington's disease mice
J. Nithianantharajah, T. Y. C. Pang, M. Zajac, C. Barkus, N. Vijiaratnam, X. Du, O. Clement, M. L. Howard, and A. J. Hannan
Howard Florey Institute, Florey Neuroscience Institutes, University of Melbourne, Parkville, VIC 3010, Australia

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion encoding a polyglutamine tract in the huntingtin protein and is the most common of at least nine polyglutamine brain diseases. HD involves selective degeneration of neurons in specific brain regions, particularly the striatum and cerebral cortex. HD patients exhibit motor abnormalities (including chorea), cognitive deficits (culminating in dementia) and psychiatric symptoms (the most common of which is depression). We have attempted to model motor, cognitive and psychiatric symptoms in the R6/1 transgenic mouse model of Huntington's disease (HD) and correlate the behavioural findings with changes in gene expression and cellular plasticity. Transgenic HD mice and wild-type littermates were compared across a range of cognitive, affective and motor tests, following housing under different environmental conditions. We have then investigated specific aspects: gene expression, neuronal morphology, synaptic plasticity and neurogenesis in selected brain regions of wild-type and HD mice, including the striatum, neocortex and hippocampus. Furthermore, our findings demonstrate that environmental factors, in particular environmental enrichment, can dramatically modify the disease process and delay the onset and progression of motor and cognitive symptoms. We have also been able to model both the cognitive deficits and affective abnormalities, and correlate them with deficits of adult neurogenesis and cortical plasticity. Cognitive and affective deficits were found to occur prior to onset of motor symptoms in HD mice and may be mediated by 'pathological plasticity' at the cellular level. We have been investigating the mechanisms mediating these experience-dependent effects, and have identified spatiotemporally regulated molecular and cellular changes in response to environmental stimulation. Our findings indicate that the modulatory effects of environmental enrichment are mediated by experience-dependent changes in transcription of specific genes, synaptogenesis and adult neurogenesis, some of which may be mimicked by a newly proposed class of therapeutics ('enviromimetics'). The relevance of these findings to chorea-acanthocytosis and related 'HD phenocopy syndromes' will be discussed.