Mitochondrial motility during synapse development

Cátia Alexandra Pinho da Silva

Research output: PhD ThesisPhD-Thesis - Research and graduation internal

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Abstract

Mammals are able to make sense of the external environment soon after they are born. How incredible is that, considering that they had not experienced anything like it before? I and others have studied young brains to understand the neuronal mechanisms that allow for this incredible feat of nature. During early brain development, connectivity between neurons is dynamic, with synaptic contacts continuously being formed and eliminated. The refinement of these synaptic connections depends on neuronal 1) activity, 2) energy, and 3) morphological changes. These are extremely important processes, as the correct synaptic contacts must be made to ensure that functional and healthy neuronal networks are formed. The work described in this thesis was conducted in the primary visual cortex of mice during the first two postnatal weeks. In this model, we are able to study 1) spontaneous activity, which is neuronal activity without sensory input nor artificial manipulations; 2) the presence and motility of mitochondria, the main energy- producing organelles in neurons; and 3) the dynamics of microtubules, the organelles responsible for neuronal morphological changes; as well as their relationship to each other. Previous work has shown that neuronal activity modulates mitochondria, and that mitochondria affect synapses. Despite their obvious importance, these studies had some experimental limitations and resulted in some apparently conflicting conclusions. In this thesis, we used an improved methodological and experimental approach, and found unifying theories for previous literature. Specifically, we showed that in vivo, mitochondrial motility decreases over development, stabilising around the second postnatal week in the visual cortex (simultaneous with eye opening). We did not find any evidence supporting the hypothesis that neuronal activity that affects the whole neuron is able to modulate mitochondrial motility during early postnatal development. And lastly, we found synaptic activity to be able to modulate mitochondrial motility, which most likely explains the developmental decrease in mitochondrial motility. Investing in learning the rules of connectivity between neurons is important and necessary. It expands humanity’s knowledge, allows for a better understanding of neurodevelopmental disorders and how to tackle them, and will certainly contribute to a reduction in the use of animal models for scientific research.
Original languageEnglish
QualificationPhD
Awarding Institution
  • Vrije Universiteit Amsterdam
Supervisors/Advisors
  • Verhage, Matthijs, Supervisor
  • Levelt, Christiaan, Co-supervisor
Award date15 Jun 2022
Publication statusPublished - 15 Jun 2022

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