Department of Molecular Physiology and Neurobiology, University of Wrocław, 50-335 Wrocław, Poland.
Laboratory of Cell Biophysics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland.
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.
长期增强作用（LTP）是记忆形成的分子基础。在这里，我们证明 LTP 严重依赖于果糖 1,6-二磷酸酶 2（Fbp2）-一种糖异生酶和多功能蛋白，保护线粒体免受应激。我们表明，LTP 诱导调节 Fbp2 与神经元线粒体和 Camk2 的关联，并且 Fbp2-Camk2 相互作用与 Camk2 自身磷酸化相关。沉默 Fbp2 表达或同时抑制和四聚化酶与模拟生理抑制剂（NAD 和 AMP）作用的合成效应物，可消除 Camk2 自身激活并阻止 LTP 的早期阶段和晚期阶段 LTP 标志物的表达。星形胶质细胞衍生的乳酸降低神经元中的 NAD/NADH 比值，从而减少四聚体 Fbp2 的池，并增加二聚体 Fbp2 的分数。因此，我们假设这种 NAD 水平依赖性的 Fbp2 二聚体/四聚体比值的增加可能是星形胶质细胞-神经元乳酸穿梭刺激 LTP 形成的关键机制。
