Cyclotraxin-B, the First Highly Potent and Selective TrkB Inhibitor, Has Anxiolytic Properties in Mice

In the last decades, few mechanistically novel therapeutic agents have been developed to treat mental and neurodegenerative disorders. Numerous studies suggest that targeting BDNF and its TrkB receptor could be a promising therapeutic strategy for the treatment of brain disorders. However, the development of potent small ligands for the TrkB receptor has proven to be difficult. By using a peptidomimetic approach, we developed a highly potent and selective TrkB inhibitor, cyclotraxin-B, capable of altering TrkB-dependent molecular and physiological processes such as synaptic plasticity, neuronal differentiation and BDNF-induced neurotoxicity. Cyclotraxin-B allosterically alters the conformation of TrkB, which leads to the inhibition of both BDNF-dependent and -independent (basal) activities. Finally, systemic administration of cyclotraxin-B to mice results in TrkB inhibition in the brain with specific anxiolytic-like behavioral effects and no antidepressant-like activity. This study demonstrates that cyclotraxin-B might not only be a powerful tool to investigate the role of BDNF and TrkB in physiology and pathology, but also represents a lead compound for the development of new therapeutic strategies to treat brain disorders

Etude du viellissement des mécanismes de la mémoire dans l'aire CA1 de l'hippocampe de rongeurs

Le vieillissement s'accompagne de troubles mnésiques. On pense aujourd'hui, que des modifications de la plasticité synoptique, sont à l'origine de ces troubles. Les récepteurs NMD A sont particulièrement important dans l'induction de cette plasticité, et notamment de la LTD (Long Term Dépression). Cette thèse montre le rôle de ces récepteurs en fonction (1) de leurs sous-unités (NR2A ou NR2B), (2) de leur localisation à la synapse (synaptique ou extrasynaptique), et (3) de l'âge des animaux (Smois vs 24mois). Nous avons aussi étudié les capacités mnésiques, la transmission et la plasticité synaptique de la souche de rats Lou/C/Jall, ayant un métabolisme et une longévité particuliers (restriction calorique continue et spontanée, et longévité moyenne de 28 mois), mais dont les capacités cognitives sont encore inconnues. Enfin, nous avons précisé le rôle de la protéine phosphatase 1 (PP1), activée en aval des récepteurs NMDA dans la modulation de la plasticité synaptique.Aging is associated with memory deficits. Alteration of synaptic plasticity is probably the basis of age-related memory deficits. NMDA receptors are particularly important in the induction of synaptic plasticity such as long term depression (LTD). The 1st aim of this PhD is to underline the role of these receptors according to (1) their subunit composition (NR2A or NR2B), (2) their localization at the synapse (synaptic or extrasynaptic), and (3) the age of the animals (3 or 24 month-old). The 2nd aim is to study mnesic capacities as well as hippocampal synaptic transmission and synaptic plasticity in the Lou/C/Jall rat strain, already studied for its specific metabolism and its longevity (rats of this strain show a natural and continuous caloric restriction, as well as a median lifespan of 28 month-old). However, their mnesic capacities are still unknown. The 3rd aim of this study is to precise the role of protein phosphatase 1 (PP1), activated downstream NMDA receptor during LTD.PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Presynaptic depression of inhibitory postsynaptic potentials by metabotropic glutamate receptors in rat hippocampal CA1 pyramidal cells

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NMDA Receptor Activation in the Aged Rat: Electrophysiological Investigations in the CA1 Area of the Hippocampal Slice Ex Vivo

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Potentiation of glutamatergic EPSPs in rat CA1 hippocampal neurons after selective cholinergic denervation by 192 IgG-saporin

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Different phosphatase-dependent mechanisms mediate long-term depression and depotentiation of long-term potentiation in mouse hippocampal CA1 area

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Synaptic functions in the aged rat hippocampus: A target for corticosteroids ?

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Glutamatergic synaptic responses and long-term potentiation are impaired in the CA1 hippocampal area of calbindin D28k-deficient mice

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Immunolesion of the cholinergic basal forebrain :effects on functional properties of hippocampal and septalneurons

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