Instituto de Investigaciones Oceanológicas, Universidad Autónoma de Baja California, Ensenada, 22860, Mexico.
Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados Del Instituto Politécnico Nacional, Ciudad de México, 07000, Mexico.
Neurochem Int. 2019 Feb;123:77-84. doi: 10.1016/j.neuint.2018.06.004. Epub 2018 Jun 13.
Glutamate, the main excitatory neurotransmitter in the vertebrate Central Nervous System, is involved in almost every aspect of brain physiology, and its signaling properties are severely affected in most neurodegenerative diseases. This neurotransmitter has to be efficiently removed from the synaptic cleft in order to prevent an over-stimulation of glutamate receptors that leads to neuronal death. Specific sodium-dependent membrane transporters, highly enriched in glial cells, elicit the clearance of glutamate. Once internalized, it is metabolized to glutamine by the glia-enriched enzyme Glutamine synthetase. Accumulated glutamine is released into the extracellular space for its uptake into pre-synaptic neurons and its conversion to glutamate that is packed into synaptic vesicles completing the glutamate/glutamine cycle. Diverse chemical compounds, like organophosphates, directly affect brain chemistry by altering levels of neurotransmitters in the synaptic cleft. Organophosphate compounds are widely used as pesticides, and all living organisms are continuously exposed to these substances, either in a direct or indirect manner. Its metabolites, like the diethyl dithiophosphate, are capable of causing brain damage through diverse mechanisms including perturbation of neuronal-glial cell interactions and have been associated with attention-deficit disorders and other mental illness. In order to characterize the neurotoxic mechanisms of diethyl dithiophosphate, we took advantage of the well characterized model of chick cerebellar Bergmann glia cultures. A significant impairment of [H] d-Aspartate transport was found upon exposure to the metabolite. These results indicate that glia cells are targets of neurotoxic substances such as pesticides and that these cells might be critically involved in the associated neuronal death.
谷氨酸是脊椎动物中枢神经系统中的主要兴奋性神经递质，参与大脑生理学的几乎各个方面，其信号特性在大多数神经退行性疾病中受到严重影响。为了防止谷氨酸受体过度刺激导致神经元死亡，这种神经递质必须从突触间隙中有效清除。特定的钠离子依赖性膜转运体在神经胶质细胞中高度丰富，引发谷氨酸的清除。一旦被内化，它就会被富含胶质的酶谷氨酸合酶代谢为谷氨酰胺。积累的谷氨酰胺被释放到细胞外间隙，以便被摄取到突触前神经元中，并转化为谷氨酸，谷氨酸被包装到突触小泡中，完成谷氨酸/谷氨酰胺循环。 有机磷化合物等多种化学化合物通过改变突触间隙中神经递质的水平直接影响大脑化学物质。有机磷化合物被广泛用作杀虫剂，所有生物都在直接或间接的方式下持续接触这些物质。其代谢物，如二乙基二硫代磷酸酯，通过多种机制导致脑损伤，包括干扰神经元-神经胶质细胞相互作用，并与注意力缺陷障碍和其他精神疾病有关。为了表征二乙基二硫代磷酸酯的神经毒性机制，我们利用了鸡小脑伯格曼神经胶质细胞培养物这一特征明确的模型。研究发现，代谢物暴露后，[H]d-天冬氨酸的转运明显受损。这些结果表明，神经胶质细胞是神经毒性物质（如杀虫剂）的靶标，这些细胞可能在相关的神经元死亡中起着至关重要的作用。
