The D-enantiomer of the amino acid serine is a novel neural modulator released by glial cells within the central nervous system (CNS). Like glycine, D-serine is a coagonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptor. D-serine is necessary fo r NMDA-receptor activation in the hippocampus and could play a critical role in synaptic plasticity, learning and memory or the pathophysiology of brain ischemia. However, the physiological function and the regulation of D-serine release in the CNS are sti ll poorly understood. Through the development of an original D-serine microsensor, I will measure the extracellular concentration of D-serine in brain slices or in the CNS of freely moving rats. The microsensor will be composed of a carbon fiber covered wi th the enzyme D-amino acid oxidase (D-AAOx). D-AAOx selectively degrades D-serine while producing H2O2 that can be detected by the carbon fiber as an index of the ambient D-serine concentration. Using this microsensor, I will determine the kinetics of D-se rine release and clearance in the CNS and examine the possibility of a functional coupling between neuronal activity and D-serine release by astrocytes. In particular, I will investigate whether stimulation of Schaffer collaterals can evoke the release of D-serine in area CA1 of the hippocampus, and whether D-serine release is correlated with the induction of long-term potentiation. By implanting this microsensor in anesthetized or freely moving rats, I will monitor D-serine release during behavioral tasks such as spatial or emotional learning, and in pathological situations like brain ischemia. Finally, the development of this microsensor will pave the way for the in vivo evaluation of potential drugs aimed at modulating D-serine levels. Overall, this proje ct will help understand the mechanisms and functions of D-serine release in the CNS and contribute to the development of new pharmacological tools targeting D-serine.
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