Redistribution of Monocarboxylate 1 and 4 in Hippocampus and Spatial Memory Impairment Induced by Long-term Ketamine Administration

Abstract

The monocarboxylate transporters (MCTs) MCT1, MCT2, and MCT4 are essential components of the astrocyte-neuron lactate shuttle (ANLS), which is a fundamental element of brain energetics. Decreased expression of MCTs can induce cognitive dysfunction of the brain. In the present study, we established a mouse model of long-term ketamine administration by subjecting mice to a 6-month course of a daily intraperitoneal injection of ketamine. These mice demonstrated learning and memory deficits and a significant decline in MCT1 and MCT4 proteins in the hippocampal membrane fraction, while cytoplasmic MCT1 and MCT4 protein levels were significantly increased. In contrast, the levels of global MCT2 protein were significantly increased. Analysis of mRNA levels found no changes in MCT1/4 transcripts, although the expression of MCT2 mRNA was significantly increased. We suggest that redistribution of hippocampal MCT1 and MCT4, but not MCT2 up-regulation, may be related to learning and memory deficits induced by long-term ketamine administration.

The potential mechanisms of lactate in mediating exercise-enhanced cognitive function: a dual role as an energy supply substrate and a signaling molecule

“…In addition to AD, some progress has been made in understanding the pathogenesis of other cognitive disorders. Mice with long-term ketamine administration showed dose-dependent learning and memory impairment as well as lower hippocampal MCT1 and MCT4 membrane protein levels and higher cytoplasmic protein levels; both MCT2 protein and mRNA levels in the hippocampus were significantly increased, suggesting that long-term ketamine administration-induced cognitive impairment may be related to abnormal expression of MCTs in the hippocampus [ 43 ]. It has also been reported that the MCTs inhibitor 4-CIN can significantly reduce the immobility time during fear contextual conditioning training, suggesting that MCTs are indispensable in the acquisition of amygdala-dependent contextual fear memory [ 44 ].…”

Low-Carbohydrate and High-Protein Diet Suppresses Working Memory Function in Healthy Mice

“…The lactate transported into neurons is used as an energy substrate for neuronal activity and as a neuro-modulator to enhance neuronal plasticity (9,(13)(14)(15)(16). Prevention of lactate supply or downregulated MCTs expression in the hippocampus causes memory dysfunction (14,15,(17)(18)(19)(20)(21)(22)(23); thus, ANLS-related glycometabolism in the hippocampus would play an important role in maintaining hippocampal function.…”

l-Lactate: Food for Thoughts, Memory and Behavior

“…Finally, mRNA analysis showed that the expression on MCT2 mRNA was significantly increased, whereas MCT1 and MCT4 transcripts displayed no changes. Supposedly, cognitive deficits observed in the behavioral tests were related to the reduced levels of hippocampal membrane MCT1 and MCT4 [110].…”