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.
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.
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.