My interest lies in the study of structure-function properties of synaptic ligand-gated ion channels, through functional approaches combining electrophysiology, molecular biology, pharmacology and thiol-modifying biochemistry. I am now exploring further this axis with structural biology tools.
During my PhD with Dr. Pierre Paoletti (CNRS, Ecole Normale Supérieure), I studied the molecular basis for the allosteric modulation of the NMDA family of glutamate receptors, which involves common molecular pathways with the desensitization of AMPA-type glutamate receptors. Proof of concepts for pharmacological modulation for those receptors are a focus of intense research, since NMDA receptors are critically involved in fundamental physiological processes such as long-term synaptic plasticity. NMDAR dysfunction is implicated in multiple brain disorders, including stroke, chronic pain and schizophrenia.
I then moved to UCL (London) for a postdoctoral stay with Prof. Trevor Smart, and investigated the molecular determinants of desensitization of Cys-loop receptors, which comprise the excitatory nicotinic acetylcholine and 5HT3 receptors, as well as the chloride-permeable GABAA and glycine receptors, which mediate fast synaptic inhibitory transmission on the brain. While activation involves a gate located in the upper half of the channel, I showed that desensitization of Cys-loop receptors involves a distinct gate located at the intracellular end of the pore, where the selectivity filter lies. Unexpectedly, such collapse of the selectivity filter is reminiscent of the slow inactivation mechanism of voltage-gated K+ and Na+ channels.
At the Pasteur Institute, most of my work now revolves around the structure-function properties of neuronal nicotinic acetylcholine receptors, which are involved in various functions such as attention and memory and whose dysfunction is associated with several neuropsychiatric and neurological disorders such as Alzheimer’s disease, schizophrenia and drug addictions.