title: Mechanisms of synaptic dysfunction and excitotoxicity in Huntington's disease.
abstract: Huntington's disease (HD) is an inherited neurodegenerative disorder of movement, mood and cognition, caused by a polyglutamine expansion in the huntingtin (Htt) protein. Genetic mouse models of HD, along with improved imaging techniques in humans at risk of, or affected by, HD, have advanced understanding of the cellular and/or molecular mechanisms underlying its pathogenesis. The striatum begins to degenerate before other brain areas, and altered activity at corticostriatal synapses contributes to an imbalance in survival versus death signaling pathways in this brain region. Striatal projection neurons of the indirect pathway are most vulnerable, and their dysfunction contributes to motor symptoms at early stages of the disease. Mutant Htt expression changes striatal excitatory synaptic activity by decreasing glutamate uptake and increasing signaling at N-methyl-d-aspartate receptors (NMDAR). A variety of studies indicate that reduced brain-derived neurotrophic factor (BDNF) transcription, transport and signaling contribute importantly to striatal neuronal dysfunction and degeneration in HD. Striatal dopamine and endocannabinoid signaling are also altered and progressively become dysfunctional. Changes at striatal neurons vary with the stage of disease and clinical symptoms. Therapeutics targeting multiple neurotransmitter signaling systems could support physiological synaptic function and delay disease onset.
authors.affiliation: Department of Psychiatry and Brain Research Centre, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
authors.forename: Marja D
authors.initials: MD
authors.lastname: Sepers
authors.affiliation: Department of Psychiatry and Brain Research Centre, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada. Electronic address: lynn.raymond@ubc.ca.
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Raymond
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000378:metabolism* / Q000473:pathology*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D004298:Dopamine