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

Spencer U. McKinstry, Yonca B. Karadeniz, Atesh K. Worthington, Volodya Y. Hayrapetyan, M. Ilcim Ozlu, Karol Serafin-Molina, W. Christopher Risher, Tuna Ustunkaya, Ioannis Dragatsis, Scott Zeitlin, Henry H. Yin, Cagla Eroglu

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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.

Original languageEnglish (US)
Pages (from-to)9455-9472
Number of pages18
JournalJournal of Neuroscience
Volume34
Issue number28
DOIs
StatePublished - Jan 1 2014

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Corpus Striatum
Huntington Disease
Synapses
Mutation
Gliosis
Neurodegenerative Diseases
Huntingtin Protein

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

McKinstry, S. U., Karadeniz, Y. B., Worthington, A. K., Hayrapetyan, V. Y., Ilcim Ozlu, M., Serafin-Molina, K., ... Eroglu, C. (2014). Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits. Journal of Neuroscience, 34(28), 9455-9472. https://doi.org/10.1523/JNEUROSCI.4699-13.2014

Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits. / McKinstry, Spencer U.; Karadeniz, Yonca B.; Worthington, Atesh K.; Hayrapetyan, Volodya Y.; Ilcim Ozlu, M.; Serafin-Molina, Karol; Christopher Risher, W.; Ustunkaya, Tuna; Dragatsis, Ioannis; Zeitlin, Scott; Yin, Henry H.; Eroglu, Cagla.

In: Journal of Neuroscience, Vol. 34, No. 28, 01.01.2014, p. 9455-9472.

Research output: Contribution to journalArticle

McKinstry, SU, Karadeniz, YB, Worthington, AK, Hayrapetyan, VY, Ilcim Ozlu, M, Serafin-Molina, K, Christopher Risher, W, Ustunkaya, T, Dragatsis, I, Zeitlin, S, Yin, HH & Eroglu, C 2014, 'Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits', Journal of Neuroscience, vol. 34, no. 28, pp. 9455-9472. https://doi.org/10.1523/JNEUROSCI.4699-13.2014
McKinstry SU, Karadeniz YB, Worthington AK, Hayrapetyan VY, Ilcim Ozlu M, Serafin-Molina K et al. Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits. Journal of Neuroscience. 2014 Jan 1;34(28):9455-9472. https://doi.org/10.1523/JNEUROSCI.4699-13.2014
McKinstry, Spencer U. ; Karadeniz, Yonca B. ; Worthington, Atesh K. ; Hayrapetyan, Volodya Y. ; Ilcim Ozlu, M. ; Serafin-Molina, Karol ; Christopher Risher, W. ; Ustunkaya, Tuna ; Dragatsis, Ioannis ; Zeitlin, Scott ; Yin, Henry H. ; Eroglu, Cagla. / Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits. In: Journal of Neuroscience. 2014 ; Vol. 34, No. 28. pp. 9455-9472.
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AU - Ilcim Ozlu, M.

AU - Serafin-Molina, Karol

AU - Christopher Risher, W.

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