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

Przemysław Duda,Agnieszka Gizak,Daniel Krowarsch,Tomasz Wójtowicz,Aleksandra Czyrek,Dariusz Rakus,Jakub Janczara

doi:10.3390/cells9061375

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.

Highlights

The late phase of Long-term potentiation (LTP), which encompasses changes lasting from minutes to hours, includes an induction of expression of a group of immediate early genes such as c-Fos, c-Jun and Arc which participate in different physiological processes associated with synaptic plasticity [4,5]
We demonstrate that hippocampal neurons express predominantly the Fbp2 isoform and that its colocalization with mitochondria is associated with the LTP induction
Since our previous study has demonstrated that Fbp2, but not Fbp1, interacts with and protects cardiomyocytic mitochondria against swelling [28]

Summary

Introduction

Long-term potentiation (LTP) in the hippocampus is the most studied example of synaptic plasticity, and it is regarded as the neuronal basis of learning [1].Molecular events underlying the early phase of LTP include glutamate-stimulated Ca2+influx into a neuron through N-methyl-D-aspartate receptors (NMDAR), subsequent activation of calcium-calmodulin-dependent protein kinase II (Camk2), and Camk2-dependent insertion of α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPAR) into the post-synaptic membrane [2,3].The late phase of LTP, which encompasses changes lasting from minutes to hours, includes an induction of expression of a group of immediate early genes such as c-Fos, c-Jun and Arc which participate in different physiological processes associated with synaptic plasticity [4,5].Cells 2020, 9, 1375; doi:10.3390/cells9061375 www.mdpi.com/journal/cells the role of crucial proteins, such as NMDAR, AMPAR and Camk, and the significance of the astrocyte-derived lactate [6] in the LTP formation have been well established, the precise mechanism underlying the persistent synaptic enhancement is not fully understood.In this paper, we present a line of evidence that fructose 1,6-bisphosphatase 2 (Fbp2) plays a crucial role in the induction and maintenance of LTP.Fbp and the second isozyme of fructose 1,6-bisphosphatase, Fbp, are regulators of gluconeogenesis. Influx into a neuron through N-methyl-D-aspartate receptors (NMDAR), subsequent activation of calcium-calmodulin-dependent protein kinase II (Camk2), and Camk2-dependent insertion of α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPAR) into the post-synaptic membrane [2,3]. The late phase of LTP, which encompasses changes lasting from minutes to hours, includes an induction of expression of a group of immediate early genes such as c-Fos, c-Jun and Arc which participate in different physiological processes associated with synaptic plasticity [4,5]. The role of crucial proteins, such as NMDAR, AMPAR and Camk, and the significance of the astrocyte-derived lactate [6] in the LTP formation have been well established, the precise mechanism underlying the persistent synaptic enhancement is not fully understood. We present a line of evidence that fructose 1,6-bisphosphatase 2 (Fbp2) plays a crucial role in the induction and maintenance of LTP. Fbp undergoes cytoplasmic–nuclear shuttling in hormone-dependent manners [9], and it has been recently demonstrated that nuclear Fbp regulates mitochondrial biogenesis via interaction with c-Myc [10]

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Conclusion