Disturbance of the glutamatergic system by glutaric acid in striatum and cerebral cortex of glutaryl-CoA dehydrogenase-deficient knockout mice: Possible implications for the neuropathology of glutaric acidemia type I

Add time:08/12/2019    Source:sciencedirect.com

The role of excitotoxicity on the neuropathology of glutaric acidemia type I (GA I) is still under debate. Therefore, in the present work, we evaluated glutamate uptake by brain slices and glutamate binding to synaptic membranes, as well as glutamine synthetase activity in cerebral cortex and striatum from glutaryl-CoA dehydrogenase deficient (Gcdh−/−) mice along development (7, 15, 30 and 60 days of life) in the hopes of clarifying this matter. We also tested the influence of glutaric acid (GA) added exogenously on these parameters. [3H]Glutamate uptake was not significantly altered in cerebral cortex and striatum from Gcdh−/− mice, as compared to WT mice. However, GA provoked a significant decrease of [3H]glutamate uptake in striatum from both WT and Gcdh−/− mice older than 7 days. This inhibitory effect was more pronounced in Gcdh−/−, as compared to WT mice. The use of a competitive inhibitor of glutamate astrocytic transporters indicated that the decrease of [3H]glutamate uptake caused by GA was due to the competition between this organic acid and glutamate for the same astrocytic transporter site. We also found that Na+-dependent [3H]glutamate binding (binding to transporters) was increased in the striatum from Gcdh−/− mice and that GA significantly diminished this binding both in striatum and cerebral cortex from Gcdh−/−, but not from WT mice. Finally, we observed that glutamine synthetase activity was not changed in brain cortex and striatum from Gcdh−/− and WT mice and that GA was not able to alter this activity. It is therefore presumed that a disturbance of the glutamatergic neurotransmission system caused by GA may potentially be involved in the neuropathology of GA I, particularly in the striatum.

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