ABSTRACT
Enhancement of NMDA Receptor Function ........................25 2.3.5 Relationship of Enhanced NMDA Receptor Activity,
Excitotoxicity, and Mhtt PolyQ Length in MSNs ...............................26 2.4 Downstream Consequences of NMDA Receptor Activation in Cells
Expressing Mhtt ..............................................................................................26 2.4.1 Effects of Mhtt on Ca2+ Homeostasis ..................................................26 2.4.2 Mitochondrial and Bioenergetic Impairment in HD ...........................27 2.4.3 Impacts of NMDA Receptor Alterations and Mitochondrial
Dysfunction on Cell Death ..................................................................29 2.5 Alterations of NMDA Receptor-Mediated Synaptic Transmission and
Plasticity in HD ...............................................................................................29 2.5.1 Changes in Corticostriatal Pathway Neurotransmission ........................29 2.5.2 Synaptic Plasticity in HD Models .......................................................... 31
2.6 Possible Mechanisms for Modulation of NMDA Receptor Function by Mhtt ................................................................................................................. 31
2.7 Summary ......................................................................................................... 32 References ................................................................................................................ 33
Huntington’s disease (HD) is an inherited, progressive neurodegenerative disorder, with a prevalence of ~5 to 10 per 100,000 people.1 This genetic, autosomal-dominant disease is caused by a mutation in exon 1 of the IT15 gene, resulting in the expansion of a CAG repeat2 encoding a polyglutamine (polyQ) region near the N-terminus of the huntingtin protein. Normal individuals have 35 or fewer CAG repeats.3 The presence of 36 or more CAG repeats leads to eventual development of the disease.4 HD is one of nine currently identified neurodegenerative diseases resulting from the expansion of a CAG tract within the coding regions of nine different genes5,6 that include the different spinocerebellar ataxias (SCAs) 1, 2, 3, 6, 7, and 17, spinal bulbar muscular atrophy (SBMA), and dentatorubral pallidoluysian atrophy (DRPLA).
