title: Cognitive Dysfunction in Huntington's Disease: Humans, Mouse Models and Molecular Mechanisms.
abstract: Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder due to an expanded CAG/polyglutamine repeat in the coding region of the huntingtin (htt) gene that causes the preferential degeneration of striatal neurons. Although HD is classically considered a motor disorder, cognitive decline manifests even before the appearance of motor symptoms, and reflects the impairment of additional neuronal populations, such as cortical and hippocampal neurons, in the presence of mutant htt (mhtt). Studies on cognitive dysfunction in HD patients have focused on the cortico-striatal pathway. Here we will describe that HD patients and mouse models share many cognitive defects. Alterations in hippocampal synaptic plasticity and function found in HD mouse models highlight that changes in the functioning of the hippocampal formation contribute to cognitive dysfunction in humans. The similarity between the cognitive dysfunction in HD patients and mouse models has helped to understand better how cognitive dysfunction takes place. Moreover, it validates the use of HD mice to study the molecular mechanisms involved in HD cognitive decline. Several studies in HD mouse models indicate that altered synaptic composition/function, deficient neurotrophic support, kinase/phosphatase imbalance, and transcription dysregulation play an important role in cognitive impairment. This knowledge opens the possibility of identifying relevant therapeutic targets to fight cognitive decline in HD. The finding that in HD many mechanisms are similarly altered in hippocampal and striatal neurons suggests the possibility of a common therapeutic strategy to ameliorate both cognitive and motor dysfunction.
authors: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.
authors: Albert
authors: A
authors: Giralt
authors: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
authors: Ana
authors: A
authors: Saavedra
authors: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
authors: Jordi
authors: J
authors: Alberch
authors: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
authors: Esther
authors: E
authors: Pérez-Navarro
mesh_terms: D000818:Animals; D003071:Cognition; D003072:Cognition Disorders / Q000209:etiology / Q000503:physiopathology*; D003342:Corpus Striatum / Q000503:physiopathology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000503:physiopathology*; D006801:Humans; D006816:Huntington Disease / Q000150:complications / Q000503:physiopathology*; D051379:Mice; D008959:Models, Neurological; D009415:Nerve Net / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009434:Neural Pathways / Q000503:physiopathology; D013045:Species Specificity; D009435:Synaptic Transmission
chemical_list: D009419:Nerve Tissue Proteins
keywords: BDNF; CBP; LTD; LTP; PKA; hippocampus; striatum