Analysis and Modeling of Dendritic Spine Morphogenesis

Abstract

Dendritic spines receive the majority of excitatory inputs in the central nervous system, and they are key structures in the regulation of neural activity. Spine morphology deficiencies are hallmark of neurodevelopemental and neurodegenerative disorders such as Autism, Fragile X - syndrome and Down's syndrome. A better understanding of spine morphogenesis can provide clues to the development of novel clinical therapies. Dendritic filopodia are the immediate precursors to spines during development. Therefore as a first step in our study, we analyzed filopodial motility in hippocampal neurons. The effect of a variety of experimental cytoskeletal drug treatments could be predicted with a simple 1D mechano-chemical model of filopodial dynamics. We then focused on three central aspects of spine morphogenesis: metamorphosis of filopodia into spines, diversity of spine shapes and their stability. To gain insight into the regulation of spine shape, we developed a 2D mechano-chemical model of spinogenesis where the actin network was modeled as a viscoelastic fluid within moving boundaries. The 2D model was then used to identify parameters and filopodia motility profiles that steer spinogenesis towards stable shapes. (supported by NIH grant P41 GM103313).