To understand brain development and function in vertebrates, a key issue is to address neuron and synapse diversity. A major breakthrough in the past years has been the development of technologies that enable the molecular dissection of neuronal networks in the mouse. Our team has contributed to this progress by developing and using innovative tools, in particular using mouse genetics, to dissect the molecular characteristics of the olivocerebellar network at the level of specific neurons and specific synapses. This network is well known for its role in motor coordination and is increasingly recognized for its involvement in cognitive processes. It is composed of a limited number of cell types connected in a very precise and stereotyped manner. Purkinje cells, the sole output of the cerebellar cortex, receive two types of excitatory inputs on distinct and non-overlapping subcellular territories: one from granule cells, through the parallel fibers, and one from inferior olivary neurons, through the climbing fibers.
The bacTRAP technology allowed us to map and compare the gene expression profiles of granule cells and inferior olivary neurons to identify specific presynaptic ligands. Synaptic protein profiling allowed the first biochemical characterization of a single type of synapse and identified the postsynaptic proteins of the parallel fiber/Purkinje cell synapse. Our team has now also developed neuron-specific genome editing in the olivocerebellar network to study gene function. Using this experimental set-up, we are aiming to identify the molecular combination characterizing each type of excitatory synapse on Purkinje cells, demonstrate its instructive role for neuronal network development and function, and analyze its modulation by neuronal activity during development. Overall, our work will decipher the mechanisms controlling synaptic identity in the mammalian brain and help us understand its modification in synaptopathies.
