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

• Grant number: 18/18500-3
• Support type: Scholarships abroad - Research Internship - Post-doctor
• Effective date (Start): January 03, 2019
• Effective date (End): January 02, 2020
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: Leonardo Resstel Barbosa Moraes
• Grantee: Cassiano Ricardo Alves Faria Diniz
• Supervisor abroad: Eero Castren
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Local de pesquisa : University of Helsinki, Finland
• Associated to the scholarship: 18/04250-5 - Study of the relevance of p75 receptor activation for the effect of fluoxetine on the extinction memory, BP.PD

Abstract

BDNF gene is translated as the precursor protein proBDNF, which is cleaved to give rise to the mature BDNF (mBDNF) and a propeptide. mBDNF (brain-derived neurotrophic factor) is crucial for the neuronal plasticity by acting on TrkB (tropomyosin receptor kinase B). Both proBDNF and propeptide trigger the p75 receptor (p75R) signaling. p75R activation usually convey physiological functional roles opposed to that observed with TrkB activation, such as neuronal shrinkage and even neuronal death. All the BDNF forms are released in the synaptic cleft in an activity-dependent fashion.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. Since the production of mBDNF is closely tied to both proBDNF and propeptide levels, it is likely that such molecules also play a role in the effect of antidepressants.Although several studies point the relevance of hippocampal mBDNF to the facilitatory effect of antidepressants on extinction memory, to our knowledge no study addressed whether the modulation of p75R signaling is also important. A few studies depicted 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 signaling.