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Modeling diffusion in cerebellar glomeruli

  • Author(s): Mitsner, Vladimir
  • et al.
Abstract

The goal of this dissertation was to examine role played by the geometry of extracellular space in influencing physiological function of neurons. Specifically we examined geometry cerebellar glomeruli - complex synaptic structure whose physiology and morphology indicate that glomerular structure may mediate glomerular function. For one cerebellar glomeruli experience tight glial ensheathment which could limit the rates of ion flow in and out of glomeruli. In addition, several lines of evidence indicate that synaptic connections within glomeruli experience cross-talk via neurotransmitter spillover. Furthermore neurotransmitter receptors whose activation could be dependent on their position as they are placed away from neurotransmitter release sites and potentially close to the neurotransmitter uptake sites. Properties described above implicate a strong relationship between the function of glomeruli and their structure. We chose to further examine this relationship in complex mathematical models of cerebellar function that preserved cerebellar geometry. Initially we used a stylized glomerular geometric model that aimed to preserve the known structural features of glomeruli. As calcium is an important second messenger that plays an integral role in synaptic plasticity, we, used the model to examine whether the structure of the glomeruli, specifically glial ensheathment could limit the flow of calcium in and out of glomeruli. In addition we investigated whether glutamate - important excitatory neurotransmitter in the glomeruli - could activate sites that lay outside of the release sites. Lastly, we extended the complexity of our model geometry by introducing morphology based on EM tomograms of rat glomeruli where we re-addressed calcium flow into glomeruli and neurotransmitter spillover. Our results using stylized model showed that calcium flow into the glomeruli is highly sensitive to the degree of glial ensheathment. Moreover, quality of ensheathment, such as the distance to which glial cells wrap around objects entering glomeruli, could influence the rate of calcium flow. We got consistent results using realistic reconstruction with calcium refilling glomeruli with 16 ms time constant. We also showed that high rates of neurotransmitter release in a stylized glomerulus could successfully activate all sites regardless of their position. While time constraints did not allow us to model multiple release events within models based on EM reconstructions, we did model a single release event that showed that activation at distal sites is dependent on the relative position of the distal sites to the release sites

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