Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, 90033, USA.
Department of Neurology, University of Southern California, 1333 San Pablo St, MCA-241, Los Angeles, CA, 90033, USA.
Mol Neurobiol. 2022 Feb;59(2):1002-1017. doi: 10.1007/s12035-021-02651-z. Epub 2021 Nov 25.
Monocarboxylate transporters (MCTs) shuttle molecules, including L-lactate, involved in metabolism and cell signaling of the central nervous system. Astrocyte-specific MCT4 is a key component of the astrocyte-neuron lactate shuttle (ANLS) and is important for neuroplasticity and learning of the hippocampus. However, the importance of astrocyte-specific MCT4 in neuroplasticity of the M1 primary motor cortex remains unknown. In this study, we investigated astrocyte-specific MCT4 in motor learning and neuroplasticity of the M1 primary motor cortex using a cell-type specific shRNA knockdown of MCT4. Knockdown of astrocyte-specific MCT4 resulted in impaired motor performance and learning on the accelerating rotarod. In addition, MCT4 knockdown was associated with a reduction of neuronal dendritic spine density and spine width and decreased protein expression of PSD95, Arc, and cFos. Using near-infrared-conjugated 2-deoxyglucose uptake as a surrogate marker for neuronal activity, MCT4 knockdown was also associated with decreased neuronal activity in the M1 primary motor cortex and associated motor regions including the dorsal striatum and ventral thalamus. Our study supports a potential role for astrocyte-specific MCT4 and the ANLS in the neuroplasticity of the M1 primary motor cortex. Targeting MCT4 may serve to enhance neuroplasticity and motor repair in several neurological disorders, including Parkinson's disease and stroke.
单羧酸转运蛋白（MCTs）转运分子，包括 L-乳酸，参与中枢神经系统的代谢和细胞信号转导。星形胶质细胞特异性 MCT4 是星形胶质细胞-神经元乳酸穿梭（ANLS）的关键组成部分，对海马体的神经可塑性和学习很重要。然而，星形胶质细胞特异性 MCT4 在 M1 初级运动皮层的神经可塑性中的重要性尚不清楚。在这项研究中，我们使用 MCT4 的细胞类型特异性 shRNA 敲低来研究 M1 初级运动皮层中的星形胶质细胞特异性 MCT4 在运动学习和神经可塑性中的作用。星形胶质细胞特异性 MCT4 的敲低导致在加速旋转棒上的运动表现和学习受损。此外，MCT4 的敲低与神经元树突棘密度和宽度的减少以及 PSD95、Arc 和 cFos 的蛋白表达降低有关。使用近红外共轭 2-脱氧葡萄糖摄取作为神经元活性的替代标志物，MCT4 的敲低也与 M1 初级运动皮层和相关运动区域（包括背侧纹状体和腹侧丘脑）中的神经元活性降低有关。我们的研究支持星形胶质细胞特异性 MCT4 和 ANLS 在 M1 初级运动皮层神经可塑性中的潜在作用。靶向 MCT4 可能有助于增强几种神经疾病（包括帕金森病和中风）中的神经可塑性和运动修复。
