Fructose 1,6-Bisphosphatase 2 Plays a Crucial Role in the Induction and Maintenance of Long-Term Potentiation

Cells. 2020 Jun 1;9(6):1375. doi: 10.3390/cells9061375.


Long-term potentiation (LTP) is a molecular basis of memory formation. Here, we demonstrate that LTP critically depends on fructose 1,6-bisphosphatase 2 (Fbp2)-a glyconeogenic enzyme and moonlighting protein protecting mitochondria against stress. We show that LTP induction regulates Fbp2 association with neuronal mitochondria and Camk2 and that the Fbp2-Camk2 interaction correlates with Camk2 autophosphorylation. Silencing of Fbp2 expression or simultaneous inhibition and tetramerization of the enzyme with a synthetic effector mimicking the action of physiological inhibitors (NAD+ and AMP) abolishes Camk2 autoactivation and blocks formation of the early phase of LTP and expression of the late phase LTP markers. Astrocyte-derived lactate reduces NAD+/NADH ratio in neurons and thus diminishes the pool of tetrameric and increases the fraction of dimeric Fbp2. We therefore hypothesize that this NAD+-level-dependent increase of the Fbp2 dimer/tetramer ratio might be a crucial mechanism in which astrocyte-neuron lactate shuttle stimulates LTP formation.

Keywords: astrocyte-neuron lactate shuttle; memory formation; moonlighting protein; protein–protein interaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Calcium / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cells, Cultured
  • Fructose-Bisphosphatase / metabolism*
  • Gene Silencing
  • Hippocampus / cytology
  • Long-Term Potentiation*
  • Membrane Potential, Mitochondrial
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Neurons / metabolism
  • Protein Binding
  • Protein Transport
  • Synapses / metabolism


  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Camk2a protein, mouse
  • Fructose-Bisphosphatase
  • Calcium