Home » Groups » Molecular Physiology of the Synapse

Molecular Physiology of the Synapse

Principal investigator: Àlex Bayés , Ph.D.

Group research focus

Our research aims to understand the molecular mechanisms governing synaptic function. We are specially interested in the proteomic study of postsynaptic protein complexes found at glutamatergic synapses, particularly the postsynaptic density, as these supra-molecular structures are key to the reception and integration of excitatory neural signals. Our methodology arises from the idea that protein complexes are highly coordinated molecular machines, which have to be understood as a whole system.

Transversal semi-thin section of a juvenile amphyoxus

Transversal semi-thin section of a juvenile amphyoxus

For this reason our research does not aim at understanding the role of a particular synaptic protein or pathway but rather ambitions to understand the organisation and dynamics of the whole postsynaptic proteome and how this governs synaptic function. Finally we are also interested in investigating how the alteration of the normal molecular function of postsynaptic complexes contributes to brain disorders, particularly to intellectual disabilities. Our recent work has importantly contributed to 2 interrelated and now well-accepted ideas. First, that the postsynaptic proteome has been highly conserved during animal evolution and, second, that mutations in genes predominantly expressed at the post-synapse are involved in many mental and behavioural disorders, specially in intellectual disability, autism spectrum disorders and schizophrenia.

Objectives

Triple staining of hippocampus from mouse

Triple staining of hippocampus from mouse

Proteomics research performed during the last ten to fifteen years has brought the field to a point in which we can consider that most synaptic proteins have been identified. Thus, with all players known, it is now time to decipher the rules that govern their collective function, thus contributing to different patterns of synaptic activity. Recent genetics studies have uncovered that many genes coding for postsynaptic proteins are involved in mental and behavioural disorders. This is particularly noticeable for disorders involving cognitive deficits such as intellectual disabilities (ID) and autism spectrum disorders (ASD). For this reason we have hypothesized that mutations in PSD components involved in disease alter the normal molecular physiology of this synaptic structure, and that reverting them should improve cognitive abilities.

When considering the proteomic study of the brain it is important to recognise that we haven’t been able to work at a spatial resolution compatible with the large cellular and molecular heterogeneity existing in this organ. It is our hypothesis that the postsynaptic proteome is highly dynamic and will vary between different neuron types, synaptic activity states or developmental stages. Yet in order to test this hypothesis it is indispensible that we develop methods to study the synapse at a much lower anatomical resolution. We are working to establish these methods. Finally, we are also very interested in studying the dynamics of the synaptic proteome during development, particularly in the context of mental disorders that progress during infancy. It is our hypothesis that events taking place early in development will be more relevant to elucidate causal mechanisms and to identify future therapeutical strategies.

Ongoing collaborative research

Publications in collaboration with network members

  • Synaptic proteomics as a means to identify the molecular basis of mental illness: Are we getting there?Reig-Viader R, Sindreu C and Bayés À.

    Synapses are centrally involved in many brain disorders, particularly in psychiatric and neurodevelopmental ones. However, our current understanding of the proteomic alterations affecting synaptic performance in the majority of mental illnesses is limited. As a result, novel pharmacotherapies with improved neurological efficacy have been scarce over the past decades.

  • Zinc transporter-1 concentrates at the postsynaptic density of hippocampal synapsesSindreu C, Bayés À, Altafaj X and Pérez-Clausell J.

    Zinc concentrates at excitatory synapses, both at the postsynaptic density and in a subset of glutamatergic boutons. Zinc can modulate synaptic plasticity, memory formation and nociception by regulating transmitter receptors and signal transduction pathways.

  • Glutamate receptor mutations in psychiatric and neurodevelopmental disordersSoto D, Altafaj X, Sindreu C and Bayés À.

    Alterations in glutamatergic neurotransmission have long been associated with psychiatric and neurodevelopmental disorders (PNDD), but only recent advances in high-throughput DNA sequencing have allowed interrogation of the prevalence of mutations in glutamate receptors (GluR) among afflicted individuals.

Recent publications