Long-Term Potentiation Requires a Rapid Burst of Dendritic Mitochondrial Fission during Induction

Synaptic transmission is bioenergetically demanding, and the diverse processes underlying synaptic plasticity elevate these demands. Therefore, mitochondrial functions, including ATP synthesis and Ca²⁺ handling, are likely essential for plasticity. Although axonal mitochondria have been extensively analyzed, LTP is predominantly induced postsynaptically, where mitochondria are understudied. Additionally, though mitochondrial fission is essential for their function, signaling pathways that regulate fission in neurons remain poorly understood. We found that NMDAR-dependent LTP induction prompted a rapid burst of dendritic mitochondrial fission and elevations of mitochondrial matrix Ca²⁺. The fission burst was triggered by cytosolic Ca²⁺ elevation and required CaMKII, actin, and Drp1, as well as dynamin 2. Preventing fission impaired mitochondrial matrix Ca²⁺ elevations, structural LTP in cultured neurons, and electrophysiological LTP in hippocampal slices. These data illustrate a novel pathway whereby synaptic activity controls mitochondrial fission and show that dynamic control of fission regulates plasticity induction, perhaps by modulating mitochondrial Ca²⁺ handling.