|Mechanisms of synaptic plasticity, and contribution to cognitive function|
José A. Esteban
Synaptic connections in the brain are continuously remodeled in response to neuronal activity. This process, known as synaptic plasticity, is widely accepted as the cellular basis for learning and memory, and it is also critical for the establishment of functional neuronal circuits during development. Additionally, several neurological and neurodegenerative diseases (such as schizophrenia, mental retardation and Alzheimer's disease) have been correlated with deficits in synaptic plasticity. Research in the laboratory is focused on the cellular and molecular processes responsible for synaptic plasticity, as a way to understand basic mechanisms underlying brain development, learning and memory.
Recent investigations have demonstrated that synaptic delivery of neurotransmitter receptors belonging to the AMPA class of glutamate receptors is a crucial element for development and synaptic plasticity in the hippocampus. The research work in the lab concentrates on the mechanisms that regulate the trafficking and synaptic delivery of AMPA receptors. Three specific projects are being addressed:
1) Identification of the signal transduction pathways that mediate receptor trafficking and synaptic delivery.
2) Identification of the cellular machinery that controls the movement and targeting of the receptors.
3) Analysis of potential alterations in synaptic plasticity mechanisms associated to cognitive disorders.
A major experimental approach in the laboratory is the expression of recombinant receptors and regulatory proteins tagged with GFP in hippocampal slices, using electrophysiology and neuronal imaging as functional assays. The laboratory has a strong multidisciplinary scope, which we believe is essential for the general goal of understanding how individual molecules contribute to neuronal function.
Selection of recent publications:
Knafo S, Sánchez-Puelles C, Palomer E, Delgado I, Draffin JE, Mingo J, Wahle T, Kaleka K, Mou L, Pereda-Perez I, Klosi E, Faber EB, Champan HM, Lozano-Montes L, Ortega-Molina A, Ordóñez-Gutiérrez L, Wandosell F, Viña J, Dotti CG, Hall RA, Pulido R, Gerges NZ, Chan AM, Spaller MR, Serrano M, Venero C, Esteban JA. PTEN recruitment controls synaptic and cognitive function in Alzheimer's models. Nat Neurosci 19, 443-453, 2016.
Science Signaling ¦ EDITORS' CHOICE
Fernández-Monreal M, Sánchez-Castillo C, Esteban JA. APPL1 gates long-term potentiation through its plekstrin homology domain. J Cell Sci 129, 2793-2803, 2016.
- Brachet A, Norwood S, Brouwers JF, Palomer E, Helms JB, Dotti CG, Esteban JA. LTP-triggered cholesterol redistribution activates Cdc42 and drives AMPA receptor synaptic delivery. J Cell Biol 208, 791-806, 2015.
- Benoist M, Palenzuela R, Rozas C, Rojas P, Tortosa E, Morales B, González-Billault C, Avila J, Esteban JA. MAP1B-dependent Rac activation is required for AMPA receptor endocytosis during long-term depression. EMBOJ 32:2287-2299, 2013.
- Fernández-Monreal M, Brown TC, Royo M, Esteban JA.The balance between receptor recycling and trafficking toward lysosomes determines synaptic strength during long-term depression. J Neurosci 32:13200-13205, 2012.
- Knafo S, Venero C, Sánchez-Puelles C, Pereda-Peréz I, Franco A, Sandi C, Suárez LM, Solís JM, Alonso-Nanclares L, Martín ED, Merino-Serrais P, Borcel E, Li S, Chen Y, Gonzalez-Soriano J, Berezin V, Bock E, DeFelipe J, Esteban JA. Facilitation of AMPA receptor synaptic delivery as a molecular mechanism for cognitive enhancement. PLoS Biology 10, doi:10.1371/journal.pbio.1001262, 2012.
NATURE | RESEARCH HIGHLIGHTS
- Jurado S, Benoist M, Lario A, Knafo S, Petrok CN and Esteban JA. PTEN is recruited to the postsynaptic terminal for NMDA receptor-dependent long-term depression. EMBOJ 29:2827-2840, 2010.
- Arendt KL, Royo M, Férnandez-Monreal M, Knafo S, Petrok CN, Martens JR and Esteban JA. PIP3 controls synaptic function by maintaining AMPA receptor clustering at the postsynaptic membrane. Nat Neurosci 13:36-44, 2010.