Role of zinc in normal and pathological synaptic transmission

Le zinc est unique dans notre organisme car à la différence des autres ions métalliques il n’existe pas seulement comme co-facteur au sein de protéines mais également sous forme libre. Ce réservoir est abondant dans le SNC où il se concentre essentiellement dans les vésicules synaptiques des neurones glutamatergiques. Le système zincergique est particulièrement abondant dans le télencéphale où il forme un réseau associationnel dense. Lors de l’activité neuronale, le zinc vésiculaire est co-libéré avec le glutamate et agit comme puissant modulateur de la transmission synaptique, notamment de par son action inhibitrice de haute affinité sur les récepteurs NMDA (rNMDA) contenant la sous-unité GluN2A. Malgré ces avancées, de nombreux points concernant le système zincergique restent mal compris. Durant cette thèse, en combinant approches d’électrophysiologie sur récepteurs recombinants et natifs, imagerie cellulaire et exploitation de nouveaux modèles de souris génétiquement modifiées, nous montrons que le zinc est un modulateur probable des synapses excitatrices sur les interneurones et que certaines populations d’interneurones (SST) sont en capacité de stocker du zinc vésiculaire. Nous montrons également que des mutations dans la sous-unité GluN2A associées à des maladies eurodéveloppementales humaines altèrent sélectivement la sensibilité des rNMDA au zinc, pointant sur l’importance du zinc vésiculaire dans le fonctionnement cérébral. Ce travail aide à notre compréhension d’un système de neuromodulation original encore peu étudié, et ouvre de nouvelles perspectives tant conceptuelles que méthodologiques sur le rôle et la distribution du zinc libre dans le cerveau.Among metal ions in the human body, zinc is unique because it does not solely exist as a co-factor inside proteins, but also as a free ion. This pool of zinc is abundant in the central nervous system where it is accumulated in the synaptic vesicles of glutamatergic neurons. The zincergic system is particularly abundant in the telencephalon where it elaborates a dense associational network. During neuronal activity, vesicular zinc is co-released with glutamate and acts as a powerful modulator of synaptic transmission due in part to its high affinity inhibition of GluN2A containing NMDA receptors (NMDARs). Despite recent advances, numerous aspects of the zincergic system remain ill defined. During the course of this thesis, by combining electrophysiological approaches on recombinant and native receptors, cell imaging and the use of new genetically modified mouse models, we show that zinc is most likely a regulator at excitatory synapses on interneurons and that some sub-populations of these interneurons (SST+) are able to store vesicular zinc. We also show that genetic mutations targeting the GluN2A subunit and that are linked to neurodevelopmental diseases in humans selectively impair NMDAR zinc sensitivity, pointing to zinc as an important regulator of brain function. This work improves our understanding of an original neuromodulatory system that remains under investigated, and opens new conceptual and methodological perspectives regarding the role and distribution of free zinc in the brain

Altered zinc sensitivity of NMDA receptors harboring clinically-relevant mutations

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Activity-dependent modulation of NMDA receptors by endogenous zinc shapes dendritic function in cortical neurons

SUMMARY Activation of NMDA receptors (NMDARs) has been proposed to be a key component of single neuron computations in vivo. However is unknown if specific mechanisms control the function of such receptors and modulate input-output transformations performed by cortical neurons under in vivo-like conditions. Here we found that in layer 2/3 pyramidal neurons (L2/3 PNs), repeated synaptic stimulation results in an activity-dependent decrease in NMDARs activity by vesicular zinc. Such a mechanism shifted the threshold for dendritic non-linearities and strongly reduced LTP induction. Modulation of NMDARs was cell- and pathway-specific, being present selectively in L2/3-L2/3 connections but absent in ascending bottom-up inputs originating from L4 neurons. Numerical simulations highlighted that activity-dependent modulation of NMDARs has an important influence in dendritic computations endowing L2/3 PN dendrites with the ability to sustain dendritic non-linear integrations constant across different regimes of synaptic activity like those found in vivo. The present results therefore provide a new perspective on the action of vesicular zinc in cortical circuits by highlighting the role of this endogenous ion in normalizing dendritic integration of PNs during a constantly changing synaptic input pattern

Early correction of synaptic long-term depression improves abnormal anxiety-like behavior in adult GluN2B-C456Y-mutant mice

© 2020 Shin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Extensive evidence links Glutamate receptor, ionotropic, NMDA2B (GRIN2B), encoding the GluN2B/NR2B subunit of N-methyl-D-aspartate receptors (NMDARs), with various neurodevelopmental disorders, including autism spectrum disorders (ASDs), but the underlying mechanisms remain unclear. In addition, it remains unknown whether mutations in GluN2B, which starts to be expressed early in development, induces early pathophysiology that can be corrected by early treatments for long-lasting effects. We generated and characterized Grin2b-mutant mice that carry a heterozygous, ASD-risk C456Y mutation (Grin2b+/C456Y). In Grin2b+/C456Y mice, GluN2B protein levels were strongly reduced in association with decreased hippocampal NMDAR currents and NMDAR-dependent long-term depression (LTD) but unaltered long-term potentiation, indicative of mutation-induced protein degradation and LTD sensitivity. Behaviorally, Grin2b+/C456Y mice showed normal social interaction but exhibited abnormal anxiolytic-like behavior. Importantly, early, but not late, treatment of young Grin2b+/C456Y mice with the NMDAR agonist D-cycloserine rescued NMDAR currents and LTD in juvenile mice and improved anxiolytic-like behavior in adult mice. Therefore, GluN2B-C456Y haploinsufficiency decreases GluN2B protein levels, NMDAR-dependent LTD, and anxiety-like behavior, and early activation of NMDAR function has long-lasting effects on adult mouse behavior11Nsciescopu