 |
|||||
|
|||||
|
|||||
|
|||||
|
|||||
Previous Article | Next Article
The Journal of Neuroscience, December 1, 2001, 21(23):9112-9123
Changes in Cortical and Striatal Neurons Predict Behavioral and Electrophysiological Abnormalities in a Transgenic Murine Model of Huntington's Disease
Genevieve A. Laforet1, Ellen Sapp3, Kathryn Chase2, Charmian McIntyre3, Frederick M. Boyce3, Mary Campbell2, Beth A. Cadigan2, Lori Warzecki2, Danilo A. Tagle4, P. Hemachandra Reddy4, Carlos Cepeda5, Christopher R. Calvert5, Eve S. Jokel5, Gloria J. Klapstein5, Marjorie A. Ariano6, Michael S. Levine5, Marian DiFiglia3, and Neil Aronin2 Departments of 1 Psychiatry and 2 Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01655, 3 Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, 4 Genetics and Molecular Biology Branch, National Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, 5 Mental Retardation Research Center, University of California at Los Angeles, Los Angeles, California 90095, and 6 Department of Neuroscience, Chicago Medical School, North Chicago, Illinois 60064
Neurons in Huntington's disease exhibit selective morphological and subcellular alterations in the striatum and cortex. The link between these neuronal changes and behavioral abnormalities is unclear. We investigated relationships between essential neuronal changes that predict motor impairment and possible involvement of the corticostriatal pathway in developing behavioral phenotypes. We therefore generated heterozygote mice expressing the N-terminal one-third of huntingtin with normal (CT18) or expanded (HD46, HD100) glutamine repeats. The HD mice exhibited motor deficits between 3 and 10 months. The age of onset depended on an expanded polyglutamine length; phenotype severity correlated with increasing age. Neuronal changes in the striatum (nuclear inclusions) preceded the onset of phenotype, whereas cortical changes, especially the accumulation of huntingtin in the nucleus and cytoplasm and the appearance of dysmorphic dendrites, predicted the onset and severity of behavioral deficits. Striatal neurons in the HD mice displayed altered responses to cortical stimulation and to activation by the excitotoxic agent NMDA. Application of NMDA increased intracellular Ca2+ levels in HD100 neurons compared with wild-type neurons. Results suggest that motor deficits in Huntington's disease arise from cumulative morphological and physiological changes in neurons that impair corticostriatal circuitry.
Key words: cortex; Huntington's disease; NMDA; neuronal morphology; striatum; transgenic mice
Copyright © 2001 Society for Neuroscience 0270-6474/01/21239112-12$05.00/0
This article has been cited by other articles:
P. R. Joshi, N.-P. Wu, V. M. Andre, D. M. Cummings, C. Cepeda, J. A. Joyce, J. B. Carroll, B. R. Leavitt, M. R. Hayden, M. S. Levine, et al.
Age-Dependent Alterations of Corticostriatal Activity in the YAC128 Mouse Model of Huntington Disease
J. Neurosci., February 25, 2009; 29(8): 2414 - 2427.
[Abstract] [Full Text] [PDF]
B. R. Miller, A. G. Walker, A. S. Shah, S. J. Barton, and G. V. Rebec
Dysregulated Information Processing by Medium Spiny Neurons in Striatum of Freely Behaving Mouse Models of Huntington's Disease
J Neurophysiol, October 1, 2008; 100(4): 2205 - 2216.
[Abstract] [Full Text] [PDF]
A. G. Walker, B. R. Miller, J. N. Fritsch, S. J. Barton, and G. V. Rebec
Altered Information Processing in the Prefrontal Cortex of Huntington's Disease Mouse Models
J. Neurosci., September 3, 2008; 28(36): 8973 - 8982.
[Abstract] [Full Text] [PDF]
A. J. Milnerwood and L. A. Raymond
Corticostriatal synaptic function in mouse models of Huntington's disease: early effects of huntingtin repeat length and protein load
J. Physiol., December 15, 2007; 585(3): 817 - 831.
[Abstract] [Full Text] [PDF]
H. B. Fernandes, K. G. Baimbridge, J. Church, M. R. Hayden, and L. A. Raymond
Mitochondrial Sensitivity and Altered Calcium Handling Underlie Enhanced NMDA-Induced Apoptosis in YAC128 Model of Huntington's Disease
J. Neurosci., December 12, 2007; 27(50): 13614 - 13623.
[Abstract] [Full Text] [PDF]
R. C. Wolf, N. Vasic, C. Schonfeldt-Lecuona, G. B. Landwehrmeyer, and D. Ecker
Dorsolateral prefrontal cortex dysfunction in presymptomatic Huntington's disease: evidence from event-related fMRI
Brain, November 1, 2007; 130(11): 2845 - 2857.
[Abstract] [Full Text] [PDF]
M. DiFiglia, M. Sena-Esteves, K. Chase, E. Sapp, E. Pfister, M. Sass, J. Yoder, P. Reeves, R. K. Pandey, K. G. Rajeev, et al.
Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits
PNAS, October 23, 2007; 104(43): 17204 - 17209.
[Abstract] [Full Text] [PDF]
J. A. Parker, M. Metzler, J. Georgiou, M. Mage, J. C. Roder, A. M. Rose, M. R. Hayden, and C. Neri
Huntingtin-Interacting Protein 1 Influences Worm and Mouse Presynaptic Function and Protects Caenorhabditis elegans Neurons against Mutant Polyglutamine Toxicity
J. Neurosci., October 10, 2007; 27(41): 11056 - 11064.
[Abstract] [Full Text] [PDF]
A. Kuhn, D. R. Goldstein, A. Hodges, A. D. Strand, T. Sengstag, C. Kooperberg, K. Becanovic, M. A. Pouladi, K. Sathasivam, J.-H. J. Cha, et al.
Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage
Hum. Mol. Genet., August 1, 2007; 16(15): 1845 - 1861.
[Abstract] [Full Text] [PDF]
M. Cyr, T. D. Sotnikova, R. R. Gainetdinov, and M. G. Caron
Dopamine enhances motor and neuropathological consequences of polyglutamine expanded huntingtin
FASEB J, December 1, 2006; 20(14): 2541 - 2543.
[Abstract] [Full Text] [PDF]
M. T. Dang, F. Yokoi, H. H. Yin, D. M. Lovinger, Y. Wang, and Y. Li
From the Cover: Disrupted motor learning and long-term synaptic plasticity in mice lacking NMDAR1 in the striatum
PNAS, October 10, 2006; 103(41): 15254 - 15259.
[Abstract] [Full Text] [PDF]
D. M. Cummings, A. J. Milnerwood, G. M. Dallerac, V. Waights, J. Y. Brown, S. C. Vatsavayai, M. C. Hirst, and K. P.S.J. Murphy
Aberrant cortical synaptic plasticity and dopaminergic dysfunction in a mouse model of huntington's disease
Hum. Mol. Genet., October 1, 2006; 15(19): 2856 - 2868.
[Abstract] [Full Text] [PDF]
C. Jacquard, Y. Trioulier, F. Cosker, C. Escartin, N. Bizat, P. Hantraye, J. M. Cancela, G. Bonvento, and E. Brouillet
Brain mitochondrial defects amplify intracellular [Ca2+] rise and neurodegeneration but not Ca2+ entry during NMDA receptor activation
FASEB J, May 1, 2006; 20(7): 1021 - 1023.
[Abstract] [Full Text] [PDF]
V. M. Andre, C. Cepeda, A. Venegas, Y. Gomez, and M. S. Levine
Altered Cortical Glutamate Receptor Function in the R6/2 Model of Huntington's Disease
J Neurophysiol, April 1, 2006; 95(4): 2108 - 2119.
[Abstract] [Full Text] [PDF]
J. M. Van Raamsdonk, Z. Murphy, E. J. Slow, B. R. Leavitt, and M. R. Hayden
Selective degeneration and nuclear localization of mutant huntingtin in the YAC128 mouse model of Huntington disease
Hum. Mol. Genet., December 15, 2005; 14(24): 3823 - 3835.
[Abstract] [Full Text] [PDF]
C. J. Zeiss
Neuroanatomical Phenotyping in the Mouse: The Dopaminergic System
Vet. Pathol., November 1, 2005; 42(6): 753 - 773.
[Abstract] [Full Text] [PDF]
H. D. Rosas, N. D. Hevelone, A. K. Zaleta, D. N. Greve, D. H. Salat, and B. Fischl
Regional cortical thinning in preclinical Huntington disease and its relationship to cognition
Neurology, September 13, 2005; 65(5): 745 - 747.
[Abstract] [Full Text] [PDF]
V. Beglopoulos, M. Montag-Sallaz, A. Rohlmann, K. Piechotta, M. Ahmad, D. Montag, and M. Missler
Neurexophilin 3 Is Highly Localized in Cortical and Cerebellar Regions and Is Functionally Important for Sensorimotor Gating and Motor Coordination
Mol. Cell. Biol., August 15, 2005; 25(16): 7278 - 7288.
[Abstract] [Full Text] [PDF]
M. A. Ariano, C. Cepeda, C. R. Calvert, J. Flores-Hernandez, E. Hernandez-Echeagaray, G. J. Klapstein, S. H. Chandler, N. Aronin, M. DiFiglia, and M. S. Levine
Striatal Potassium Channel Dysfunction in Huntington's Disease Transgenic Mice
J Neurophysiol, May 1, 2005; 93(5): 2565 - 2574.
[Abstract] [Full Text] [PDF]
J. M. Van Raamsdonk, J. Pearson, E. J. Slow, S. M. Hossain, B. R. Leavitt, and M. R. Hayden
Cognitive Dysfunction Precedes Neuropathology and Motor Abnormalities in the YAC128 Mouse Model of Huntington's Disease
J. Neurosci., April 20, 2005; 25(16): 4169 - 4180.
[Abstract] [Full Text] [PDF]
N. K. Mazarakis, A. Cybulska-Klosowicz, H. Grote, T. Pang, A. Van Dellen, M. Kossut, C. Blakemore, and A. J. Hannan
Deficits in Experience-Dependent Cortical Plasticity and Sensory-Discrimination Learning in Presymptomatic Huntington's Disease Mice
J. Neurosci., March 23, 2005; 25(12): 3059 - 3066.
[Abstract] [Full Text] [PDF]
J.-C. Lievens, T. Rival, M. Iche, H. Chneiweiss, and S. Birman
Expanded polyglutamine peptides disrupt EGF receptor signaling and glutamate transporter expression in Drosophila
Hum. Mol. Genet., March 1, 2005; 14(5): 713 - 724.
[Abstract] [Full Text] [PDF]
G. J. Klapstein and M. S. Levine
Age-Dependent Biphasic Changes in Ischemic Sensitivity in the Striatum of Huntington's Disease R6/2 Transgenic Mice
J Neurophysiol, February 1, 2005; 93(2): 758 - 765.
[Abstract] [Full Text] [PDF]
R. Chiesa, P. Piccardo, S. Dossena, L. Nowoslawski, K. A. Roth, B. Ghetti, and D. A. Harris
Bax deletion prevents neuronal loss but not neurological symptoms in a transgenic model of inherited prion disease
PNAS, January 4, 2005; 102(1): 238 - 243.
[Abstract] [Full Text] [PDF]
N. Bizat, J.-M. Hermel, S. Humbert, C. Jacquard, C. Creminon, C. Escartin, F. Saudou, S. Krajewski, P. Hantraye, and E. Brouillet
In Vivo Calpain/Caspase Cross-talk during 3-Nitropropionic Acid-induced Striatal Degeneration: IMPLICATION OF A CALPAIN-MEDIATED CLEAVAGE OF ACTIVE CASPASE-3
J. Biol. Chem., October 31, 2003; 278(44): 43245 - 43253.
[Abstract] [Full Text] [PDF]
H. Li, T. Wyman, Z.-X. Yu, S.-H. Li, and X.-J. Li
Abnormal association of mutant huntingtin with synaptic vesicles inhibits glutamate release
Hum. Mol. Genet., August 15, 2003; 12(16): 2021 - 2030.
[Abstract] [Full Text] [PDF]
E. J. Slow, J. van Raamsdonk, D. Rogers, S. H. Coleman, R. K. Graham, Y. Deng, R. Oh, N. Bissada, S. M. Hossain, Y.-Z. Yang, et al.
Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease
Hum. Mol. Genet., July 1, 2003; 12(13): 1555 - 1567.
[Abstract] [Full Text] [PDF]
N. Bizat, J.-M. Hermel, F. Boyer, C. Jacquard, C. Creminon, S. Ouary, C. Escartin, P. Hantraye, S. Kajewski, and E. Brouillet
Calpain Is a Major Cell Death Effector in Selective Striatal Degeneration Induced In Vivo by 3-Nitropropionate: Implications for Huntington's Disease
J. Neurosci., June 15, 2003; 23(12): 5020 - 5030.
[Abstract] [Full Text] [PDF]
Z.-X. Yu, S.-H. Li, J. Evans, A. Pillarisetti, H. Li, and X.-J. Li
Mutant Huntingtin Causes Context-Dependent Neurodegeneration in Mice with Huntington's Disease
J. Neurosci., March 15, 2003; 23(6): 2193 - 2202.
[Abstract] [Full Text] [PDF]
C. Cepeda, R. S. Hurst, C. R. Calvert, E. Hernandez-Echeagaray, O. K. Nguyen, E. Jocoy, L. J. Christian, M. A. Ariano, and M. S. Levine
Transient and Progressive Electrophysiological Alterations in the Corticostriatal Pathway in a Mouse Model of Huntington's Disease
J. Neurosci., February 1, 2003; 23(3): 961 - 969.
[Abstract] [Full Text] [PDF]
C. L. Wellington, L. M. Ellerby, C.-A. Gutekunst, D. Rogers, S. Warby, R. K. Graham, O. Loubser, J. van Raamsdonk, R. Singaraja, Y.-Z. Yang, et al.
Caspase Cleavage of Mutant Huntingtin Precedes Neurodegeneration in Huntington's Disease
J. Neurosci., September 15, 2002; 22(18): 7862 - 7872.
[Abstract] [Full Text] [PDF]
E. Y.W. Chan, R. Luthi-Carter, A. Strand, S. M. Solano, S. A. Hanson, M. M. DeJohn, C. Kooperberg, K. O. Chase, M. DiFiglia, A. B. Young, et al.
Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington's disease
Hum. Mol. Genet., August 15, 2002; 11(17): 1939 - 1951.
[Abstract] [Full Text] [PDF]
|
|
|
|
 |
|