Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits.
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.
Type
Journal articleSubject
corticostriatal connectionsexcitatory synapses
huntingtin
reactive gliosis
synapse maturation
synaptogenesis
Animals
Cells, Cultured
Cerebral Cortex
Corpus Striatum
Excitatory Postsynaptic Potentials
Huntingtin Protein
Mice
Mice, Transgenic
Nerve Tissue Proteins
Nuclear Proteins
Synapses
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https://hdl.handle.net/10161/10231Published Version (Please cite this version)
10.1523/JNEUROSCI.4699-13.2014Publication Info
McKinstry, Spencer U; Karadeniz, Yonca B; Worthington, Atesh K; Hayrapetyan, Volodya
Y; Ozlu, M Ilcim; Serafin-Molina, Karol; ... Eroglu, Cagla (2014). Huntingtin is required for normal excitatory synapse development in cortical and striatal
circuits. J Neurosci, 34(28). pp. 9455-9472. 10.1523/JNEUROSCI.4699-13.2014. Retrieved from https://hdl.handle.net/10161/10231.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Cagla Eroglu
Chancellor's Distinguished Professor of Cell Biology
Henry Yin
Professor of Psychology and Neuroscience
I am interested in understanding the neural mechanisms underlying goal-directed actions.
For the first time in history, advances in psychology and neurobiology have made
it feasible to pursue the detailed neural mechanisms underlying goal-directed and
voluntary actions--how they are driven by the needs and desires of the organism and
controlled by cognitive processes that provide a rich representation of the self and
the world. My approach to this problem is highly integrative, combining behav
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