PKCδ is an activator of neuronal mitochondrial metabolism that mediates the spacing effect on memory consolidation

Abstract

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 PKCδ, a member of the so-called ‘novel PKC’ family of enzymes, which uncovers the critical function of PKCδ in neurons as a regulator of mitochondrial metabolism for LTM. Additionally, PKCδ 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, PKCδ signaling binds the cognitive and metabolic constraints underlying LTM formation into a unified gating mechanism.

Mitochondrial Ca2+efflux controls neuronal metabolism and long-term memory across species

“…Similar to rodent neurons in vitro (Figure 2J, K), we quantified pyruvate accumulation rates in vivo as a readout of cytosol-to-mitochondria pyruvate flux by blocking mitochondrial pyruvate import 15 (Figure 3D). We confirmed that 3 hours after 1x training, mitochondrial pyruvate import was not accelerated in α/β neurons of wild-type flies (Figure 3D, left panel), as previously reported 68 . To examine the effect of reducing Letm1 expression in this paradigm, we expressed Pyronic together with an RNAi conditionally targeting Letm1 exclusively in adult α/β neurons in adults 74 (see Materials and Methods).…”

“…A short 1x training session causes a quick rise in pyruvate absorption by mitochondria 67 that is temporary and no longer detectable three hours after conditioning 68 . The 5x spaced training, in contrast, leads to an extended period of metabolic activation observable up to 8 hours after conditioning 68 . This long-lasting upregulation in the metabolic state of MB neurons is a critical early step that enables the formation of LTM 15 .…”

“…We next sought to establish in vivo the role of Letm1 in controlling neuronal metabolism in firing neurons and assess its putative impact on brain function and behavior. Over the recent years, memory formation following classical Pavlovian aversive olfactory conditioning in Drosophila melanogaster [64][65][66] has emerged as a key example of a cognitive function that is modulated by neuronal metabolism 15,67,68 . Following the paired delivery of an odor and an electric shock, flies form an avoidance memory that is encoded in neurons of the mushroom body (MB), a major integrative center of insect brains that is considered functionally analogous to the mammalian hippocampus 69,70 .…”

“…However, this metabolic activation is complexly connected with how long the memory lasts. A short 1x training session causes a quick rise in pyruvate absorption by mitochondria 67 that is temporary and no longer detectable three hours after conditioning 68 . The 5x spaced training, in contrast, leads to an extended period of metabolic activation observable up to 8 hours after conditioning 68 .…”

“…The lack of sustained metabolic increases in MB neurons after olfactory training precludes the success of long-term memory formation 15,68 . This concept presents two major predictions with respect to Letm1 function: 1) Letm1 KD flies, which already present a marked increase in MB metabolism after 1x training (Figure 3D, E), should be capable of forming LTM in these conditions, and 2) the absence of Letm1 should not modulate other shorter-lived types of memories that do not require long-lasting adaptations in metabolism, such as middle-term memory (MTM) 15,68 . To examine this hypothesis, we first measured MTM 3h after 1x training and found no significant behavioral differences between wild-type and Letm1 KD flies, as expected (Figure 4A, B, left panel).…”