Kontou, Georgina; (2018) Miro1-dependent Mitochondrial Dynamics in Parvalbumin Interneurons. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Parvalbumin interneurons are fast-spiking inhibitory cells that have been implicated in the generation of rhythmic network activity in the γ-frequency band (30-80Hz) by coordinating principal cell activity. In order to sustain their high firing rates, parvalbumin interneurons have a high mitochondrial content reflecting their large energy utilization. Therefore, parvalbumin interneurons are more susceptible to incidents of mitochondrial impairment as mitochondria provide the predominant source of energy. Miro1 is a Ca²⁺-sensing adaptor protein that links mitochondria to the trafficking apparatus, for their microtubule-dependent transport along axons and dendrites, in order to meet the metabolic needs of the cell. Here, we explore the role of Miro1 in parvalbumin interneurons and how changes in the mitochondrial distribution could alter network activity. To investigate mitochondrial dynamics we generated a mouse line where mitochondria are specifically labelled in parvalbumin interneurons. The Cre- recombinase is expressed exclusively in parvalbumin interneurons and excises a termination signal upstream of a fluorescent reporter allowing for the visualisation of mitochondria only in these cells. We further crossed this line with the Miro1(f/f) mouse, generating a transgenic mouse where Miro1 was conditionally knocked-out exclusively in parvalbumin interneurons. Specifically we investigated the conditional removal of Miro1 in mitochondrial dynamics in parvalbumin interneurons. Using live-imaging of ex-vivo organotypic brain cultures, we demonstrated a reduction in mitochondrial trafficking in parvalbumin interneurons in the hippocampus under basal conditions. This lead to accumulation of mitochondria in the soma and their depletion from synaptic terminals. Loss of Miro1 resulted in alterations in axonal but not dendritic branching in parvalbumin interneurons. This was accompanied by altered synaptic transmission and increased frequency of γ-oscillations in hippocampal brain slices. In this study, we show for the first time that Miro1 and Miro1-dependent mitochondrial positioning are essential for correct parvalbumin interneuron function and network activity.

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