Biophysics of Dendritic Spine Morphogenesis

Released on by Olena Marchenko
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  • Biophysics of Dendritic Spine Morphogenesis Book Detail

  • Author : Olena Marchenko
  • Release Date : 2017
  • Publisher :
  • Genre : Electronic dissertations
  • Pages :
  • ISBN 13 :
  • File Size : 48,48 MB
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Biophysics of Dendritic Spine Morphogenesis by Olena Marchenko PDF Summary

Book Description: Dendritic spines receive the majority of synaptic inputs in the mammalian central nervous system and constitute the foundation for a healthy nervous system. Cognitive and motor delays, and other symptoms of impaired neurodevelopment are associated with abnormal dendritic spine shape and densities. Understanding of spine stability and spine formation in neurodevelopmental conditions remains elusive. Spine formation is determined by the stability of its transient precursor: the dendritic filopodium. First, we aim to understand dendritic filopodium motility and stability mechanism that underlies its transition into a spine. We hypothesized that mechanical feedback among the actin retrograde flow, myosin activity, and substrate adhesion gives rise to various filopodial behaviors. We have formulated a minimal one-dimensional partial differential equation model that reproduces the range of observed motility. The model predicts the response of the system to each of these experimental perturbations, supporting the hypothesis that our actomyosin-driven mechanism controls dendritic filopodia dynamics and therefore identifies the main parameters in spine formation and stability. Spine development is deficient in Angelman (AS) and overabundant in Dup15q Syndromes as suggested by the corresponding animal models. In human cells, the phenotypic outcome and the timepoint in neurodevelopment at which the phenotype emerges, have not previously been studied. Therefore, we investigated dendritic spine morphology in Dup15q and AS human induced pluripotent stem cell (hiPSC)-derived neurons, characterizing filopodia motility, spine shape, maturation and neurite branching at different time points of development. Our findings suggest that the first phenotypic differences in Dup15q Syndrome arise during early neurodevelopment at week 7 with increased dendritic filopodia density and protrusion/retraction rates compared to control. We further show that the spine number and density are increased in Dup15q and decreased in AS. For future studies, syndrome-specific spine formation can be explored with a morphologically realistic 2-dimensional partial differential equation model of a dendritic spine solved on moving boundaries.

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