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Molecular mechanisms involved in the downregulation of glutamate AMPA receptors at synapses during induction of long-term depression (LTD) in hippocampal cells

Grant number: 12/17186-7
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): November 01, 2012
Effective date (End): October 31, 2015
Field of knowledge:Biological Sciences - Morphology - Cytology and Cell Biology
Principal Investigator:Luis Lamberti Pinto da Silva
Grantee:Luciana Previato de Almeida
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated scholarship(s):14/03327-3 - Role of AP-2 and ESCRT machinery in the down-regulation of glutamate AMPA receptors at synapses during mGluR-induced long-term depression (LTD) in hippocampal cells, BE.EP.PD


Synaptic plasticity involves changes in synaptic strength, which are required in memory and learning processes. These long-term modifications can result in increase (long-term potentiation or LTP) or decrease (long-term depression or LTD) in the strength of synaptic transmission which is regulated by the availability of AMPA receptors (AMPAR) in the postsynaptic membranes. The density of AMPAR at synapses is determined by mechanisms of endocytosis, recycling and degradation of these receptors. These processes are altered in neurodegenerative disorders such as in Alzheimer's disease, leading to deficits in synaptic transmission. It has been shown that AMPAR subunits GluA1 and GluA2 are ubiquitinated during the internalization. Ubiquitination serves as signal for incorporation of several cell surface receptors into intraluminal vesicles of late endosomes during downregulation. In many cases, this process requires the action of the ESCRT machinery and leads to lysosomal targeting of the receptor. Here we propose to investigate the mechanisms controlling AMPAR selection to either recycling or degradative pathways during LTD, specifically studying the role of ubiquitination and the ESCRT machinery in these events. With the work proposed here, we will contribute to a better understanding of the trafficking mechanisms that lead to AMPAR downregulation during LTD, which could reveal new targets for Alzheimer´s disease treatment. (AU)

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