Calcium signalling plays an important role in dendritic development and establishment of neural circuit connectivity through transcriptional regulation and cytoskeletal remodelling. AMP-activated protein kinase (AMPK) is known to regulate mitochondrial dynamics and function and has been implicated in neurodegenerative diseases. Here, Mineko Kengaku and colleagues demonstrate a link between activity-dependent dendritic development and AMPK-dependent mitochondrial homeostasis in rodent hippocampus. First, by blocking neuronal activity in dissociated hippocampal neurons, the authors observe decreased dendritic outgrowth and abnormally elongated mitochondria. Then, the authors knock down AMPK in cultured neurons and observe defective dendritic formation and impaired mitochondrial fission — a process important for generating new mitochondria and removing damaged or aged mitochondria through mitophagy. Simultaneous live imaging of calcium and AMPK activity shows that calcium spikes triggered by neuronal activity are synchronised with AMPK activity oscillations in dendrites. This AMPK oscillation can be inhibited by knocking down CaMKK2, a kinase upstream of AMPK. Finally, the authors find that AMPK activation by neuronal activity leads to phosphorylation of the mitochondrial fission factor MFF and the autophagy-initiating kinase ULK1, which in turn initiate mitochondrial fission and mitophagy. Overall, the findings suggest that neuronal activity tunes AMPK activity to regulate mitochondrial homeostasis in developing dendrites of hippocampal neurons.
