Title

Virtual NEURON: A unifying computational framework to study calcium signaling and membrane electrophysiology in physiological cerebellar Purkinje neurons and IP3R1-associated ataxias

Date of Completion

January 2012

Keywords

Biology, Cell

Degree

Ph.D.

Abstract

Ataxia, or motor incoordination, affects approximately 150,000 Americans and hundreds of thousands of individuals worldwide. Affected individuals are deprived of normal coordination of motor function, such as speaking, writing, holding a cup of hot coffee without spilling, climbing stairs without tumbling, or needing the use of walking aids from as early as mid-childhood. A handful of more common hereditary ataxias are linked in some way to reduced abundance of the inositol 1,4,5-triphosphate receptor 1 (IP3R1) or increased sensitivity of the receptor to activation by its ligand Inositol 1,4,5-triphosphate (IP3). These findings suggest that IP3R1 insufficiency or hypersensitivity may contribute to the pathophysiology of various forms of spinocerebellar ataxia (SCA). The purpose of this computational study was to use the Virtual Cell and NEURON modeling and simulation frameworks to (i) create models that reflect the physiological production of IP3 from hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2), and link the appropriate IP3 signal to IP3R1-mediated calcium release in cerebellar Purkinje spines, (ii) develop a strategy to merge biochemical modeling with electrophysiology in the simulations, and use this merge to explore interactions between calcium release and membrane potential, (iii) determine whether adjusting IP3R1 sensitivity (in the context of insufficiency) or abundance (in the context of hypersensitivity) could restore normal calcium transients and postsynaptic currents in cerebellar Purkinje spines. In addition, a framework was created that unifies disparate observations about IP3R1 abundance and sensitivity in a number of SCAs. Results from our study may help to explain findings in mice, and after extensive laboratory study, may ultimately be translated to ataxic individuals. Our work lays a foundation for using computation to tackle the problems of (a) understanding cellular pathophysiology of spinocerebellar ataxias and (b) suggesting ways to restore normal cellular and electrophysiological responses that are based on experimental observations, and that can potentially lead to development of new therapeutics for treating ataxia. ^