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

Abstract

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.

Expression of Fbp2, a Newly Discovered Constituent of Memory Formation Mechanisms, Is Regulated by Astrocyte–Neuron Crosstalk

“…To make sure that the CCCP-and oligomycin A-induced changes in Fbp2 localization are comparable to alterations that we have previously observed in neurons during LTP induction [6], we used these two factors to treat neurons and obtained similar results ( Figure 5A).…”

“…In contrast to total cellular ROS, we observed a small but statistically significant (17%, p < 0.01; Figure S1) elevation of mitochondrial ROS production under the tested conditions. It is well documented that, in cardiomyocytes and neurons, Fbp2 binds to mitochondria and protects them against Ca 2+ -or ROS-induced excessive depolarization that can lead to swelling of the organelles [1,[4][5][6]. Thus, the observed increase in mitochondrial ROS production was not unexpected and reflected a weaker protection of mitochondria resulting from the lowered amount of Fbp2 protein in astrocytes.…”

“…We found that, in the co-culture, the chemical induction of LTP significantly elevated mRNA for Fbp2 in neurons, but not in astrocytes ( Figure 2). Both neuronal Fbp2 and astrocytes are indispensable parts of neuronal plasticity machinery (LTP) [6,8]; thus, we asked if LTP induction affects the expression of mRNA for Fbp2 in neurons and astrocytes. We found that, in the co-culture, the chemical induction of LTP significantly elevated mRNA for Fbp2 in neurons, but not in astrocytes ( Figure 2).…”

“…Recently, we have demonstrated that the presence of Fbp2, presumably its dimeric form, in hippocampal neurons is indispensable for N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) formation in the hippocampus [6]. LTP, the most studied example of synaptic plasticity, is regarded as the neuronal basis of learning [7].…”

“…Dimeric Fbp2, in turn, can interact with neuronal calcium/calmodulin-dependent protein kinase 2 (Camk2), which correlates with Camk2 autophosphorylation. Silencing of Fbp2 expression or simultaneous inhibition and tetramerization of the enzyme in neurons abolishes Camk2 autoactivation and blocks formation of the early phase of LTP and expression of the late-phase LTP markers [6]. We have thus hypothesized that the NAD + level-dependent change in the neuronal Fbp2 dimer/tetramer ratio might be a crucial mechanism by which astrocyte-neuron lactate shuttle regulates LTP formation, making Fbp2 a hub linking neuronal signaling with redox and/or energetic state of brain during the formation of memory traces [6].…”