PKC[delta] is an activator of neuronal mitochondrial metabolism that mediates the spacing effect on memory consolidation

Relevance-based selectivity and high energy cost are two distinct features of long-term memory (LTM) formation that warrant its default inhibition. Spaced repetition of learning is a highly conserved cognitive mechanism that can lift this inhibition. Here, we questioned how the spacing effect integrates experience selection and energy efficiency at the cellular and molecular levels. We showed in Drosophila that spaced training triggers LTM formation by extending over several hours an increased mitochondrial metabolic activity in neurons of the associative memory center, the mushroom bodies (MBs). We found that this effect is mediated by PKC[delta], a member of the so-called 'novel PKC' family of enzymes, which uncovers the critical function of PKC[delta] in neurons as a regulator of mitochondrial metabolism for LTM. Additionally, PKC[delta] activation and translocation to mitochondria result from LTM-specific dopamine signaling on MB neurons. By bridging experience-dependent neuronal circuit activity with metabolic modulation of memory-encoding neurons, PKC[delta] signaling binds the cognitive and metabolic constraints underlying LTM formation into a unified gating mechanism.