Higgs, N; (2016) Miro dependent mitochondrial positioning is important for neuronal development and maintenance. Doctoral thesis , UCL (University College London).

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Abstract

Correct dendritic development is important for the formation of neuronal circuits. Dendritic arbors form an extensive, complex network with spatially distinct compartments that cannot be sustained by diffusion of energy from the soma alone. Mitochondria are highly dynamic organelles, important for providing energy, buffering intracellular calcium and playing a role in apoptosis. These organelles must be actively transported and localised throughout the neuron to match their energy and calcium buffering requirements. Miro (mitochondrial Rho) GTPases have been identified as central regulators of mitochondrial trafficking, important for the activity dependent transport and distribution of these organelles within the neuron. However the role of mitochondrial trafficking for correct neuronal development, maintenance and survival is poorly understood. This thesis describes the development and characterisation of novel genetic strategies, including multi-cistronic vectors and viral probes, to investigate mitochondrial dynamics within dissociated neurons and in the cells of an intact system, such as organotypic brain slices. This has been combined with the use of mouse genetics to investigate the roles played by Miro proteins in both developing and mature neurons. Miro1 deletion caused the depletion of mitochondria from distal dendrites but not axons, accompanied by a marked reduction in dendritic complexity. Postnatal deletion of Miro1 led to a progressive loss of dendrites, initially affecting the most distal dendrites and eventually resulting in compromised neuronal survival. These effects were greatly enhanced upon double deletion of both Miro1 and Miro2, highlighting their necessary and co-operative roles for dendritic maintenance. Surprisingly, even though Miro1 knock-out neurons showed an aberrant dendritic morphology there were no alterations in spine density compared to wild-type neurons. Conversely, loss of Miro2 increased the spine density of cultured neurons, in vitro, and hippocampal pyramidal CA1 neurons, in vivo, revealing an important role of Miro2 in the regulation of spines. Together this work demonstrates that the Miro proteins are essential for correct neuronal structure and connectivity.

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