Introduction To Hd

HD is an autosomal dominant, progressive and fatal neurodegenerative disease. The classic clinical features of adult onset HD include involuntary choreic movements and motor incoordination that progress to severe bradykinesia and rigidity. Emotional disturbance, personality changes, and dementia are prevalent and may be the first indications of illness, often many years prior to motor

'Department of Psychiatry and Brain Research Centre, University of British Columbia, 2255 Wesbrook Mall, Vancouver, Canada, V6T 1X7; [email protected]

symptoms. Presently there is no cure and no effective treatment, and death occurs following ~20 years of inexorable decline.

The incidence of HD is 5-10 in every 100,000 people; however, HD is one of an increasing number of similar neurodegenerative diseases caused by triplet repeat expansions. HD follows Mendelian autosomal dominant inheritance. Exon 1 of the HD gene includes a polymorphic CAG repeat1, which translates to a tract of glutamine residues (polyglutamine repeat; polyQ) in the protein huntingtin (htt). HD gene carriers have larger repeats than normal individuals, and there is a negative correlation between repeat length and age of onset: adult onset (20-80 years) is attributed to >36 polyQ, while juvenile onset (2-20 years) generally occurs with >70 repeats. The neuropathology of HD is most evident in the corpus striatum of the basal ganglia, a group of interconnected nuclei involved in motor coordination, cognitive function, and subcortical memory processes. The most vulnerable striatal cells are GABAergic medium-sized spiny projection neurons (MSNs), which receive extensive glutamatergic input from all cortical areas and represent the main striatal output. HD pathology is classified grade 0-4 post mortem, ranging from no microscopic changes at grade 0 (despite substantial clinical evidence) to 95% loss of MSNs in grade 42. HD is a severe neurodegenerative disease; however, recent advances suggest that many clinical features of the disease correlate best with cellular dysfunction prior to cell death.

This chapter reviews leading theories current to our understanding of synaptic dysfunction in HD. The chapter is constructed around a simplified distinction between pre- and postsynaptic function at the cortico-striatal synapse. Due to the synaptic focus, much evidence reviewed here was derived from mouse models of HD. Each model recapitulates different characteristics of human HD, and the severity of phenotype is inversely proportional to HD gene transcript length and directly proportional to polyQ repeat load and expression levels (reviewed in ref. 3); a comparison of their basic characteristics is outlined in Table 1.

Table 1. Summary of Referenced HD Mouse Models.

Age at onset (months)

Table 1. Summary of Referenced HD Mouse Models.

Age at onset (months)







R6/2, R6/1

150, 120

N-terminal tg

<1, 2.5

1, 4.5

4, >12

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