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Study of the relevance of p75 receptor activation for the effect of antidepressants on the extinction memory

Grant number: 18/04250-5
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Start date: July 01, 2018
End date: June 30, 2022
Field of knowledge:Biological Sciences - Pharmacology - Neuropsychopharmacology
Principal Investigator:Leonardo Resstel Barbosa Moraes
Grantee:Cassiano Ricardo Alves Faria Diniz
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated scholarship(s):18/18500-3 - Study of the relevance of p75 receptor activation for the effect of fluoxetine on the extinction memory, BE.EP.PD

Abstract

BDNF (Brain-Derived Neurotrophic Factor) is a neurotrophin crucial for to the neuronal plasticity by acting on TrkB (Tropomyosin receptor kinase B). BDNF gene is firstly translated as the precursor protein proBDNF, which is cleaved to give rise to the mature BDNF (mBDNF) and a propeptide. Such as mBDNF, proBDNF also can be released in the synaptic cleft in an activity-dependent fashion. In case, proBDNF binds to the p75 receptor (p75R). The activation of p75R usually convey physiological functional roles opposed to the downstream signaling from TrkB, such as neuronal shrinkage and even neuronal death. Indeed, downstream signaling related to the p75R activation is also described to trigger neuronal shrinkage and neuronal death. Beyond mBDNF, proBDNF cleavage give rise to the propeptide, whose release is also verified in the synaptic cleft in an activity-dependent fashion. The propeptide may also act on the p75R. Chronic treatment with antidepressants induce an increase of hippocampal mBDNF/TrkB levels relevant to their therapeutical effect . However, it was observed that both fluoxetine and imipramine, beyond to increase hippocampal neurogenesis (action dependent of mBDNF/TrkB signaling), are also able to promote the neuronal apoptosis. So far, we do not have knowledge about any pathway involved with this death's effect seen with antidepressant treatment. Since the production of mBDNF is tied to proBDNF and to the formation of the propeptide, it's likely that both proBDNF and propeptide also play a role in the effect of antidepressants. Although several studies point to the relevance of hippocampal mBDNF on the effectiveness of antidepressants concerning extinction memory, to our knowledge no study addressed whether the modulation of p75R signaling has also importance to that effect. In fact, few studies approach the pertinence of p75R signaling to the extinction memory. Therefore, this work aims to evaluate if the effectiveness of fluoxetine to enhance the extinction memory depend on the modulating of the hippocampal p75R activation. A parallel aim is evaluate if fluoxetine treatment is also able to increase the expression or the release of proBDNF and/or propeptide. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CASAROTTO, PLINIO C.; GIRYCH, MYKHAILO; FRED, SENEM M.; KOVALEVA, VERA; MOLINER, RAFAEL; ENKAVI, GIRAY; BIOJONE, CAROLINE; CANNAROZZO, CECILIA; SAHU, MADHUSMITA PRYIADRASHINI; KAURINKOSKI, KATJA; et al. Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. Cell, v. 184, n. 5, p. 1299+, . (18/04250-5, 18/18500-3)
DINIZ, CASSIANO R. A. F.; BIOJONE, CAROLINE; JOCA, SARNIA R. L.; RANTAMAKI, TOMI; CASTREN, EERO; GUIMARAES, FRANCISCO S.; CASAROTTO, PLINIO C.. Dual mechanism of TRKB activation by anandamide through CB1 and TRPV1 receptors. PeerJ, v. 7, . (13/02549-0, 18/04250-5, 11/02746-4, 13/01029-2)