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

Publication ,  Journal Article
McKinstry, SU; Karadeniz, YB; Worthington, AK; Hayrapetyan, VY; Ozlu, MI; Serafin-Molina, K; Risher, WC; Ustunkaya, T; Dragatsis, I; Zeitlin, S ...
Published in: J Neurosci
July 9, 2014

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.

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Published In

J Neurosci

DOI

EISSN

1529-2401

Publication Date

July 9, 2014

Volume

34

Issue

28

Start / End Page

9455 / 9472

Location

United States

Related Subject Headings

  • Synapses
  • Nuclear Proteins
  • Neurology & Neurosurgery
  • Nerve Tissue Proteins
  • Mice, Transgenic
  • Mice
  • Huntingtin Protein
  • Excitatory Postsynaptic Potentials
  • Corpus Striatum
  • Cerebral Cortex
 

Citation

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McKinstry, S. U., Karadeniz, Y. B., Worthington, A. K., Hayrapetyan, V. Y., Ozlu, M. I., Serafin-Molina, K., … Eroglu, C. (2014). Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits. J Neurosci, 34(28), 9455–9472. https://doi.org/10.1523/JNEUROSCI.4699-13.2014
McKinstry, Spencer U., Yonca B. Karadeniz, Atesh K. Worthington, Volodya Y. Hayrapetyan, M Ilcim Ozlu, Karol Serafin-Molina, W Christopher Risher, et al. “Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits.J Neurosci 34, no. 28 (July 9, 2014): 9455–72. https://doi.org/10.1523/JNEUROSCI.4699-13.2014.
McKinstry SU, Karadeniz YB, Worthington AK, Hayrapetyan VY, Ozlu MI, Serafin-Molina K, et al. Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits. J Neurosci. 2014 Jul 9;34(28):9455–72.
McKinstry, Spencer U., et al. “Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits.J Neurosci, vol. 34, no. 28, July 2014, pp. 9455–72. Pubmed, doi:10.1523/JNEUROSCI.4699-13.2014.
McKinstry SU, Karadeniz YB, Worthington AK, Hayrapetyan VY, Ozlu MI, Serafin-Molina K, Risher WC, Ustunkaya T, Dragatsis I, Zeitlin S, Yin HH, Eroglu C. Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits. J Neurosci. 2014 Jul 9;34(28):9455–9472.

Published In

J Neurosci

DOI

EISSN

1529-2401

Publication Date

July 9, 2014

Volume

34

Issue

28

Start / End Page

9455 / 9472

Location

United States

Related Subject Headings

  • Synapses
  • Nuclear Proteins
  • Neurology & Neurosurgery
  • Nerve Tissue Proteins
  • Mice, Transgenic
  • Mice
  • Huntingtin Protein
  • Excitatory Postsynaptic Potentials
  • Corpus Striatum
  • Cerebral Cortex