The influence of presynaptic mitochondria on synapse formation, stabilization and elimination in (360G-Wellcome-105386_Z_14_A)

Mitochondria are found at many presynaptic terminals and are known to influence synaptic function. However, we do not know how and when mitochondria are recruited to synapses and whether that recruitment influences synaptic longevity. Long-term stabilisation of a newlyformed synapse represents a novel, persistent means of communication in the brain, and has been proposed to underlie memory or learning. Therefore, we wish to test the hypothesis that targeted trafficking and retention of mitochondria at a presynaptic terminal is required to establish an enduring, functional synapse in the central nervous system. To do this, we will use live cell imaging of axons, which have been transfected/transduced with fluorescent markers for mitochondria and presynaptic terminals. Our goal is to track mitochondrial recruitment to synapses as they turn over. Longitudinal in vitro and intravital imaging of neurons will be used to establish the timecourse of mitochondrial recruitment and its relationship with synaptic stabilisation. Finally, optogenetic control of mitochondrial anchoring will be used to control synaptic mitochondrial retention and thereby influence synapse stability to demonstrate their inter-dependence. In this way, the importance of a stable pool of synaptic mitochondria for synaptic turnover will be demonstrated, with potential implications for learning, cognition and neurodegenerative disease.