Astrocyte-derived lactate/NADH alters methamphetamine-induced memory consolidation and retrieval by regulating neuronal synaptic plasticity in the dorsal hippocampus

• Published in: Brain Structure and Function 2022-11, Vol.227 (8), p.2681-2699
• Main Authors: Tan, Xu, Liu, Xiaoyu, Liu, E, Liu, Min, Mu, Shouhong, Hang, Zhaofang, Han, Weikai, Wang, Tingting, Zhang, Yang, Zhang, Jing, Yue, Qingwei, Sun, Jinhao
• Format: Article
• Language: English
• Subjects: Addictions; Animal memory; Axonal transport; Biomedical and Life Sciences; Biomedicine; Cell Biology; Energy resources; Gene expression; Glutamic acid receptors (ionotropic); Glycogen; Glycogen phosphorylase; Hippocampal plasticity; Hippocampus; Lactic acid; Long-term potentiation; Methamphetamine; Microinjection; N-Methyl-D-aspartic acid receptors; Neurology; Neuroplasticity; Neurosciences; Oligonucleotides; Original Article; Phosphorylase; Place preference conditioning; Redox properties; Synaptic plasticity
• ISSN: 1863-2653; 1863-2661; 0340-2061
• DOI: 10.1007/s00429-022-02563-1

Drug memory is associated with drug-taking experience and environmental cues, which mainly contribute to addiction. Recent studies report that glycogenolysis-derived lactate from astrocyte transport to neurons is necessary for long-term potentiation and memory formation instead of its function as an energy substrate. However, the role of astrocyte-neuron lactate transfer in neuronal plasticity and methamphetamine (METH)-induced addiction memory consolidation and retrieval, especially the underlying mechanisms, are not clear. C57BL/6 J mice trained for METH-induced conditioned place preference (CPP) were stereotaxically injected with the glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) into the dorsal hippocampus (dHPC) 15 min before training. The CPP score was recorded, and neuronal synaptic plasticity was detected with Golgi staining. The neuronal Ca 2+ levels were examined using AAV-GCaMP6 injection. Moreover, monocarboxylate transporters (MCT1, MCT2, MCT4) were inhibited with oligodeoxynucleotides in the dHPC to further prove the METH appetitive memory changes. The data showed that inhibiting lactate transport by microinjection with DAB or monocarboxylate transporter oligodeoxynucleotides in the dHPC completely destroyed METH-induced CPP, reduced Npas4 and other plasticity-associated gene expression and decreased neuronal Ca 2+ levels and neuronal arborization and spine density, all of which were fully rescued by L-lactate coadministration except for MCT2-ODN administration. Furthermore, the downstream signaling molecule NADH could mimic lactate’s effects and trigger METH CPP by influencing the redox state of neurons and regulating NMDA receptor activity. Collectively, these findings indicate that astrocyte-neuron lactate transfer is crucial for METH-induced memory consolidation and retrieval.