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Molecular and cellular mechanisms for synaptic plasticity

Principal investigator: José A. Esteban , Ph.D.

Group research focus

My research group has a longstanding interest in the molecular and cellular mechanisms of synaptic plasticity, and their contribution to cognitive processes such as learning and memory. Using electrophysiological, imaging and molecular techniques, we have made important contributions to understand how the membrane trafficking machinery of the neuron controls synaptic function by shuttling neurotransmitter receptors in and out of the synaptic membrane.

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Co-expression of GFP and Amyloid Precursor Protein (APP) in hippocampal slices. With this system we assess functional changes at synapses due to excessive production of beta-amyloid in neurons.

In particular we have identified a highly compartimentalized endosomal network that carries out the bidirectional movement of AMPA-type glutamate receptors during long-term potentiation and long-term depression (Gerges et al, J Biol Chem 2004; Brown et al, Neuron 2005; Gerges et al, EMBOJ 2006; Brown et al, J Neurosci 2007; Fernández-Monreal et al, J Neurosci 2012). This movement is powered by motor proteins and assisted by cytoskeletal elements (Correia et al, Nat Neurosci 2008; Benoist et al, EMBOJ 2013). We have also identified the PI3K-PTEN pathway as a critical regulator of this process (Arendt et al, Nat Neurosci 2010; Jurado et al, EMBOJ 2010). Interestingly, lipid components of intracellular membranes also participate in the regulation of membrane protein trafficking during synaptic plasticity. Thus, we found that cholesterol metabolism is regulated by synaptic activity and mediates the mobilization of intracellular neurotransmitter receptors towards the synaptic membrane (Brachet et al, J Cell Biol 2015).

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A major experimental system in the laboratory is the expression of neurotransmitter receptors and regulatory proteins tagged with GFP in hippocampal slices, using electrophysiology and fluorescence imaging as functional assays.

We are also particularly interested in how these processes impact on cognitive function. In this direction, we recently found that facilitation of neurotransmitter receptor trafficking enhances synaptic plasticity and improves cognitive performance in healthy animals (Knafo et al, PloS Biol 2012).

Objectives

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Morphological analysis of GFP-tagged AMPA receptors in dendritic spines from hippocampal slices.

We now know that several cognitive disorders, such as mental retardation, autism or Alzheimer’s disease, are associated to deficits in synaptic plasticity. Therefore, we are exploiting this molecular and cellular information on synaptic plasticity mechanisms to develop potential therapeutic avenues for cognitive enhancement. These new research lines will involve a deeper understanding of the relevant neuronal circuit dynamics, and the development of appropriate behavioral models and in vivo manipulations. In this context, the interaction with the other members of the SynCogDys network will be instrumental for the success of this endeavor. As a whole, we are interested in understanding how molecular mechanisms operate at the synapse and contribute to brain function in health and disease. This general goal will be greatly benefitted by our participation in this network.

Ongoing collaborative research

Recent publications