Editors' ChoiceNeuroscience

Fasting, translation control, and seizures

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Sci. Signal.  03 Jan 2017:
Vol. 10, Issue 460, eaam6552
DOI: 10.1126/scisignal.aam6552

Acute fasting, a therapy that helps some epilepsy patients, inhibits protein translation and dampens synaptic activity in neuromuscular junctions in flies.

Caloric restriction and intermittent fasting seem to have various beneficial health effects, including improved immune system function, enhanced cognitive function, and even reduced episodes of seizures in some children with epilepsy. A ketogenic diet has long been prescribed as a method to control seizures, but patients that are less responsive to the ketogenic diet benefit from intermittent fasting. Using flies, Kauwe et al. explored this neuronal effect of fasting and found that cellular stress caused by short-term fasting suppressed synaptic activity at the neuromuscular junction (NMJ) by inhibiting postsynaptic protein translation. In the NMJ in Drosophila and vertebrates, synaptic strength between motor neurons and muscle is affected by retrograde signals from the muscle. In response to reduced neurotransmitter reception, muscle can signal back to the presynaptic motor neuron to increase neurotransmitter release to maintain homeostasis. Experimentally in Drosophila, this retrograde compensation mechanism can be triggered by muscle-specific overexpression of target of rapamycin (TOR), which senses various nutrients and promotes protein translation by phosphorylating and inhibiting eukaryotic initiation factor 4E (eIF4E)–binding protein (4E-BP). In this study by Kauwe et al., various genetic and electrophysiological experiments in Drosophila revealed that a few hours of fasting, but not amino acid restriction alone, blocked retrograde synaptic compensation and dampened NMJ synaptic activity in a manner dependent on reduced protein translation in the postsynaptic muscle, which was mediated by reduced TOR activity and increased Fork-head box O (FoxO)–mediated transcription of 4E-BP. Acute fasting did not alter synaptic structure. The findings might explain the beneficial effects of fasting in some children that suffer from seizures and may lead to new therapies for epilepsy and other NMJ-related diseases. Fasting was a popular remedy for seizures and other ailments in ancient Greece; now, roughly two millennia later, we are beginning to uncover molecular mechanisms that might justify this as a sound approach.

In the Science Signaling archives, other work has highlighted the contribution of translational control on synaptic activity and cognition. Bowling et al. found that the antipsychotic drug haloperidol stimulated the translation of mRNAs encoding cytoskeletal proteins, and subsequently increased neuronal complexity, by activating the mammalian TOR complex 1 (mTORC1) in primary striatal dopaminergic neurons. mTORC1-dependent translation is implicated in synaptic plasticity, memory consolidation, and autism. A review by Santini and Klann highlight how reciprocal interactions between protein synthesis and synaptic activity appear to contribute to autism spectrum disorder. Tudor et al. found that mTORC1-dependent suppression of 4E-BP and the subsequent increase in protein synthesis in the hippocampus mediates the formation of memories in mice; the authors also found that sleep deprivation impairs this mechanism and hence impairs learning. Given the new findings of Kauwe et al., it may be possible that fasting affects cognition also through the mTORC1–4E-BP axis. Future work may reveal how to translate this knowledge into therapies (pun intended).

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