title: Striatal synaptic dysfunction and altered calcium regulation in Huntington disease.
abstract: Synaptic dysfunction and altered calcium homeostasis in the brain is common to many neurodegenerative disorders. Among these, Huntington disease (HD), which is inherited in an autosomal dominant fashion, can serve as a model for investigating these mechanisms. HD generally manifests in middle age as a disorder of movement, mood and cognition. An expanded polymorphic CAG repeat in the HTT gene results in progressive neurodegeneration that impacts striatal spiny projection neurons (SPNs) earliest and most severely. Striatal SPNs receive massive glutamatergic input from cortex and thalamus, and these excitatory synapses are a focus for early changes that can trigger aberrant downstream signaling to disrupt synaptic plasticity and lead to later degeneration. Mitochondrial dysfunction and altered intracellular calcium-induced calcium release and sequestration mechanisms add to the impairments in circuit function that may underlie prodromal cognitive and subtle motor deficits. These mechanisms and implications for developing disease-modifying therapy will be reviewed here.
authors.affiliation: Department of Psychiatry and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 4834-2255 Wesbrook Mall, Vancouver, BC, Canada, V6T 1Z3. Electronic address: lynn.raymond@ubc.ca.
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Raymond
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism / Q000503:physiopathology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000502:physiology*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D002118:Calcium
keywords: Excitatory synapse; Inositol tri-phosphate (IP3) receptor; Mitochondria; NMDA receptor; Ryanodine receptor; glutamate transporters