Neuronal Changes in Lactate Dehydrogenase B Deficiency Mice
The main energy source of the brain is glucose; however, it has been reported that neurons also metabolize lactate. Lactate is an anion that is supplied by astrocytes, as described by the astrocyte-to-neuron lactate shuttle hypothesis. Lactate dehydrogenase B (LDHB), contained within neurons, converts lactate to pyruvate to be utilized as an energy source. Accordingly, the utilization of lactate as energy source by neurons of LDHB knock-out (KO) mice may be limited. We hypothesized that a deficiency in LDHB would decrease neuronal function and induced histological changes in LDHB KO mice.
Behavioral tests included an open field test, a Morris water maze test, and a Y maze test, which were performed at 15-18 months of age. We analyzed histological alterations in hippocampal neurons and glial cells using cresyl violet staining for quantification of cell numbers, and identified oxidative stress markers (e.g., nitrotyrosine and 8-hydroxy-deoxyguanosine). We also compared lactate peaks in the hippocampus using magnetic resonance spectroscopy. Histological tests and magnetic resonance spectroscopy were performed at 19-22 months of age.
As results, the open field test revealed decreased locomotor motion LDHB KO mice compared to WT mice. Moreover, the Morris water maze test showed diminished spatial memory and non-spatial memory in LDHB KO mice compared to WT mice. The histological analyses showed that neuronal cells in LDHB KO mice appeared smaller and darker than that of WT mice. In addition, there were fewer astrocytes in the hippocampus of LDHB KO mice. Expression of the reactive oxygen species-related marker, 3-nitrotyrosine, tended to increase in the neurons of LDHB KO mice compared to WT mice. Magnetic resonance spectroscopy results showed increased ratio of hippocampal lactate/ N-acetyl aspartate ratio in LDHB KO mice compared to WT mice.
The increase of reactive oxygen species found in hippocampal neurons might mediate the observed alterations in neuronal morphology and behavioral deterioration, and ultimately, could result in the acceleration of brain aging in aged LDHB KO mice.
