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J Neurosci. 2014 Jul 9;34(28):9455-72. doi: 10.1523/JNEUROSCI.4699-13.2014.

Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits.

Author information

1
Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710.
2
Department of Psychology and Neuroscience, Faculty of Arts and Sciences, Duke University, Durham, North Carolina 27710.
3
Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710.
4
Department of Physiology, University of Tennessee, Health Science Center, Memphis, Tennessee 38163.
5
Department of Neuroscience, University of Virginia, School of Medicine, Charlottesville, Virginia 22908, and.
6
Department of Psychology and Neuroscience, Faculty of Arts and Sciences, Duke University, Durham, North Carolina 27710, Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, Duke Institute for Brain Sciences, Durham, North Carolina 27710.
7
Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, Duke Institute for Brain Sciences, Durham, North Carolina 27710 cagla.eroglu@dm.duke.edu.

Abstract

Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of a poly-glutamine (poly-Q) stretch in the huntingtin (Htt) protein. Gain-of-function effects of mutant Htt have been extensively investigated as the major driver of neurodegeneration in HD. However, loss-of-function effects of poly-Q mutations recently emerged as potential drivers of disease pathophysiology. Early synaptic problems in the excitatory cortical and striatal connections have been reported in HD, but the role of Htt protein in synaptic connectivity was unknown. Therefore, we investigated the role of Htt in synaptic connectivity in vivo by conditionally silencing Htt in the developing mouse cortex. When cortical Htt function was silenced, cortical and striatal excitatory synapses formed and matured at an accelerated pace through postnatal day 21 (P21). This exuberant synaptic connectivity was lost over time in the cortex, resulting in the deterioration of synapses by 5 weeks. Synaptic decline in the cortex was accompanied with layer- and region-specific reactive gliosis without cell loss. To determine whether the disease-causing poly-Q mutation in Htt affects synapse development, we next investigated the synaptic connectivity in a full-length knock-in mouse model of HD, the zQ175 mouse. Similar to the cortical conditional knock-outs, we found excessive excitatory synapse formation and maturation in the cortices of P21 zQ175, which was lost by 5 weeks. Together, our findings reveal that cortical Htt is required for the correct establishment of cortical and striatal excitatory circuits, and this function of Htt is lost when the mutant Htt is present.

KEYWORDS:

corticostriatal connections; excitatory synapses; huntingtin; reactive gliosis; synapse maturation; synaptogenesis

PMID:
25009276
PMCID:
PMC4087216
DOI:
10.1523/JNEUROSCI.4699-13.2014
[Indexed for MEDLINE]
Free PMC Article

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