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

• Grant number: 14/03327-3
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Effective date (Start): June 01, 2014
• Effective date (End): May 31, 2015
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Luis Lamberti Pinto da Silva
• Grantee: Luciana Previato de Almeida
• Supervisor: Sônia Aparecida Lopes Corrêa
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Research place: University of Bradford, England
• Associated to the scholarship: 12/17186-7 - Molecular mechanisms involved in the downregulation of glutamate AMPA receptors at synapses during induction of long-term depression (LTD) in hippocampal cells, BP.PD

Abstract

Synaptic plasticity involves dynamic changes in synaptic strength, which are thought to be involved in memory and learning processes, and can last for a long period of time. Long-term increase in synaptic strength (long-term potentiation or LTP) or decrease (long-term depression or LTD) are regulated by the availability of ±-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPAR) in the postsynaptic membranes. The density of AMPAR at synapses is determined by mechanisms of insertion, endocytosis, recycling and degradation of these receptors. AMPARs are composed of four subunits, most GluA1/GluA2 heteromers. The cytoplasmic tail of the subunit GluA2 is known to interact with the ¼2 subunit of the clathrin adaptor complex AP-2 and this interaction is involved in NMDA receptor-induced internalization of GluA2 in cultured neurons. In addition, AMPAR subunits GluA1 and GluA2 are ubiquitinated during the internalization. Ubiquitination serves as signal for incorporation of several cell surface receptors into intralumenal vesicles of late endosomes. For most cell surface receptors that undergo ubiquitin-mediate down-regulation, this process requires the action of the ESCRT machinery and leads to lysosomal targeting. Here we propose to investigate the mechanisms controlling AMPAR selection to degradative pathways during mGluR-LTD, specifically studying the role of AP-2 and the ESCRT machinery in these events. The work proposed here complements my postdoctoral studies funded by FAPESP (2012/17186-7) and will contribute to a better understanding of molecular mechanisms underlying AMPAR trafficking which may reveal new targets to slow down deficits in cognition observed in ageing and in neurodegenerative diseases such as Alzheimer´s disease. (AU)