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.

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Citation

Published Version (Please cite this version)

10.1523/JNEUROSCI.4699-13.2014

Publication Info

McKinstry, Spencer U, Yonca B Karadeniz, Atesh K Worthington, Volodya Y Hayrapetyan, M Ilcim Ozlu, Karol Serafin-Molina, W Christopher Risher, Tuna Ustunkaya, et al. (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.

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Scholars@Duke

Yin

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 behavioral analysis with electrophysiological techniques as well as tools from molecular biology. In the near future three techniques will be emphasized. 1) Dissecting reward-guided behavior using analytical behavioral assays. 2) In vivo recording from cerebral cortex, thalamus, midbrain, and basal ganglia in awake behaving rodents. Up to hundreds of neurons can be recorded from multiple brain areas that form a functional neural network in a single animal. 3) In vitro (and ex vivo) whole-cell patch-clamp recording in brain slices, with the aid of genetic tools for visualization of distinct neuronal populations. Ultimately, I hope to characterize goal-directed actions at multiple levels of analysis--from molecules to neural networks. This knowledge will provide us with insight into various pathological conditions characterized by impaired goal-directed behaviors, such as drug addiction, obsessive-compulsive disorder, Parkinson's disease, and Huntington's disease.

Eroglu

Cagla Eroglu

Chancellor's Distinguished Professor of Cell Biology

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