The addition and removal of synapses is fundamental to learning and memory formation in the adult mammalian neocortex. This experience-dependent structural plasticity of pre- and post-synaptic terminals changes neuronal circuit organisation. Structural plasticity of dendritic spines has been well-studied but the mechanisms driving presynaptic structural plasticity are not understood. Mitochondria are suitable candidates for regulation of presynaptic plasticity as they are small, fragmented organelles that can be positioned differentially to modulate individual terminals. They have been directly implicated in regulating presynaptic activity due to their roles in energy and calcium homeostasis. Based on the hypothesis that local mitochondria may influence synapse formation and/or loss, the studies presented here have investigated the relationship between axonal mitochondria and structural plasticity of presynaptic boutons. Light microscopy was used to track their formation and persistence in rodent neurons in vitro and in vivo alongside the trafficking and anchoring of mitochondria to assess their relationship to presynaptic structural plasticity. Electron microscopy techniques were also developed to obtain correlated spatial information that complemented the temporal dynamics of live light microscopy. Presynaptic terminals of cortical neurons were found to be highly dynamic, being lost and gained within hours in vitro, and days in vivo. The numbers of mitochondria and presynaptic terminals were strongly correlated in vivo due to local anchoring of mitochondria at approximately 40% of all terminals. The longevity of those terminals was also positively correlated with the presence of presynaptic mitochondria in vivo, but not in vitro. This suggests that, as boutons are formed, persist and become long-lived in vivo, they increasingly accumulate mitochondria to regulate their activity. Understanding these relationships is essential to unpicking the molecular mechanisms of learning, perception and memory formation in the neocortex as well as interpreting the aetiology of mitochondrial-related neurological diseases.
|Date of Award||23 Jan 2019|
- The University of Bristol
|Supervisor||Michael C Ashby (Supervisor)|