Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits.
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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.
Excitatory Postsynaptic Potentials
Nerve Tissue Proteins
Published Version (Please cite this version)10.1523/JNEUROSCI.4699-13.2014
Publication InfoDragatsis, I; Eroglu, C; Hayrapetyan, Volodya; Karadeniz, YB; McKinstry, SU; Ozlu, MI; ... Zeitlin, S (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 http://hdl.handle.net/10161/10231.
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Associate Professor of Cell Biology
Associate Professor in the Department 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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