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Functional identification of GluN3A subunit-containing NMDA receptors in the adult brain

Abstract : NMDA receptors (NMDARs) are glutamate-gated ion channels of the CNS. The best characterized and most common forms of NMDARs are composed by two GluN1 subunits binding glycine and two GluN2 subunits binding glutamate. Our attention focused on the less known glycine-binding GluN3A subunit of the third NMDAR group. GluN3A can form two distinct NMDAR flavors. First, GluN3A can constitute diheteromeric GluN1/GluN3ARs activated by glycine and insensitive to glutamate. GluN3A can also generate with GluN1 and GluN2 glutamate-sensitive triheteromeric GluN1/GluN2/GluN3ARs with different properties from classic NMDARs. GluN3A expression is assumed to be limited to the first postnatal weeks. Therefore, its identification in neurons has so far been limited to the juvenile brain, where triheteromers were shown to play a role in synaptic maturation. GluN1/GluN3ARs had however never been identified in native tissues. During my thesis, on the basis of novel immunohistological evidence on GluN3A expression in the adult brain, and using a unique compound, CGP78608, I showed that GluN1/GluN3ARs are functional in several nuclei, comprising the adult Medial Habenula and juvenile hippocampus. Concerning GluN1/GluN2/GluN3ARs, I could demonstrate that they are functional in the paraventricular nucleus of the adult thalamus. Among several cell subgroups examined, I could show that neurons expressing calbindin 2 and melanocortin receptors 4 from the parabrachial nucleus are physiological activators of these receptors. In conclusion, my work led to a shift in our perception of how GluN3A subunits are expressed and opens new hypotheses on how they can contribute to the activity of neural circuits.
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Submitted on : Tuesday, September 27, 2022 - 1:02:08 AM
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  • HAL Id : tel-03788730, version 1

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Sarah Abi Gerges. Functional identification of GluN3A subunit-containing NMDA receptors in the adult brain. Neuroscience. Sorbonne Université, 2020. English. ⟨NNT : 2020SORUS259⟩. ⟨tel-03788730⟩

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