Neuronal degeneration in the basal ganglia and loss of pallido- subthalamic synapses in mice with targeted disruption of the Huntington's disease gene

John R. O'Kusky, Jamal Nasir, Francesca Cicchetti, Andre Parent, Michael R. Hayden

    Research output: Contribution to journalArticle

    Abstract

    Huntington's disease (HD) is a progressive neurodegenerative disorder associated with CAG repeat expansion within a novel gene (IT15). We have previously created a targeted disruption in exon 5 of Hdh (Hdh(ex5)), the murine homologue of the HD gene. Homozygotes for the Hdh(ex5) mutation exhibit embryolethality before embryonic day 8.5, while heterozygotes survive to adulthood and display increased motor activity and cognitive deficits. Detailed morphometric and stereological analyses of the basal ganglia in adult heterozygous mice were performed by light and electron microscopy. Morphometric analyses demonstrated a significant loss of neurons from both the globus pallidus (29%) and the subthalamic nucleus (51%), with a normal complement of neurons in the caudate-putamen and substantia nigra. The ultrastructural appearance of sporadic degenerating neurons in these regions indicated apoptosis. The highest frequency of apoptotic neurons was observed in the globus pallidus and subthalamic nucleus. Stereological analyses in the subthalamic nucleus revealed a significant decrease in the numerical density of symmetric synapses (43%), suggesting a relatively selective loss of inhibitory pallido-subthalamic afferents. Immunohistochemistry using antibodies against enkephalin and substance-P was unremarkable in heterozygotes, indicating a normal complement of enkephalin-immunoreactive striatopallidal afferents and substance-P-immunoreactive striatopeduncular and striatonigral afferents in these animals. These findings show that loss of an intact huntingtin protein is associated with significant morphological alterations in the basal ganglia of adult mice, indicating an important role for this protein during development of the central nervous system.
    Original languageEnglish
    Pages (from-to)468-479
    Number of pages12
    JournalBrain Research
    Volume818
    Issue number2
    DOIs
    Publication statusPublished - 13 Feb 1999

    Fingerprint

    Huntington Disease
    Basal Ganglia
    Subthalamic Nucleus
    Synapses
    Neurons
    Globus Pallidus
    Enkephalins
    Heterozygote
    Substance P
    Genes
    Putamen
    Homozygote
    Substantia Nigra
    Neurodegenerative Diseases
    Exons
    Electron Microscopy
    Motor Activity
    Central Nervous System
    Immunohistochemistry
    Apoptosis

    Keywords

    • Apoptosis
    • Huntingtin protein
    • Huntington's disease
    • Subthalamic nucleus

    Cite this

    O'Kusky, John R. ; Nasir, Jamal ; Cicchetti, Francesca ; Parent, Andre ; Hayden, Michael R. / Neuronal degeneration in the basal ganglia and loss of pallido- subthalamic synapses in mice with targeted disruption of the Huntington's disease gene. In: Brain Research. 1999 ; Vol. 818, No. 2. pp. 468-479.
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    abstract = "Huntington's disease (HD) is a progressive neurodegenerative disorder associated with CAG repeat expansion within a novel gene (IT15). We have previously created a targeted disruption in exon 5 of Hdh (Hdh(ex5)), the murine homologue of the HD gene. Homozygotes for the Hdh(ex5) mutation exhibit embryolethality before embryonic day 8.5, while heterozygotes survive to adulthood and display increased motor activity and cognitive deficits. Detailed morphometric and stereological analyses of the basal ganglia in adult heterozygous mice were performed by light and electron microscopy. Morphometric analyses demonstrated a significant loss of neurons from both the globus pallidus (29{\%}) and the subthalamic nucleus (51{\%}), with a normal complement of neurons in the caudate-putamen and substantia nigra. The ultrastructural appearance of sporadic degenerating neurons in these regions indicated apoptosis. The highest frequency of apoptotic neurons was observed in the globus pallidus and subthalamic nucleus. Stereological analyses in the subthalamic nucleus revealed a significant decrease in the numerical density of symmetric synapses (43{\%}), suggesting a relatively selective loss of inhibitory pallido-subthalamic afferents. Immunohistochemistry using antibodies against enkephalin and substance-P was unremarkable in heterozygotes, indicating a normal complement of enkephalin-immunoreactive striatopallidal afferents and substance-P-immunoreactive striatopeduncular and striatonigral afferents in these animals. These findings show that loss of an intact huntingtin protein is associated with significant morphological alterations in the basal ganglia of adult mice, indicating an important role for this protein during development of the central nervous system.",
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    Neuronal degeneration in the basal ganglia and loss of pallido- subthalamic synapses in mice with targeted disruption of the Huntington's disease gene. / O'Kusky, John R.; Nasir, Jamal; Cicchetti, Francesca; Parent, Andre; Hayden, Michael R.

    In: Brain Research, Vol. 818, No. 2, 13.02.1999, p. 468-479.

    Research output: Contribution to journalArticle

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    AU - Nasir, Jamal

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    AU - Parent, Andre

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