Synapse identity and complexity in the mammalian brain
Molecular identity of synapses
Our team is using the olivo-cerebellar network as a model system. This network is composed of a limited number of cell types connected in a very precise and stereotyped manner. Each of these neuronal types can be specifically targeted in genetically modified mice using BAC drivers already described in the GENSAT database (www.gensat.org). Purkinje cells, the sole output of the cerebellar cortex, receive two types of excitatory inputs, one from the granule cells through the parallel fibers, and one from the inferior olivary neurons, through the climbing fibers. These two types of excitatory synapses have clear differences in terms of their physiology and form on separate dendritic territories on Purkinje cells.
Studying this network at the synaptic level enables the development of tools to identify its role in motor function and cognition and in the etiology of brain diseases.
Our model: diversity of excitatory synapses in cerebellar Purkinje cells.
New molecular determinants of synapse identity
To fully characterize the molecular determinants of synapse identity in Purkinje cells, our aim is to provide a comprehensive description of the molecular composition of each type of excitatory synapses at the presynaptic and postsynaptic level.
At the presynaptic level, we have performed a comparative analysis of gene expression profiles of granule cells and inferior olivary neurons using the bacTRAP strategy that allowed us to identify candidates that might contribute to synapse specificity (Veleanu, Urrieta-Chavez, Sigoillot et al. 2022). Further work has shown that 1) there is a presynaptic molecular combination specific to each excitatory synapse type on a given neuron, 2) this combination is made of secreted molecules that can modulate non-redundant signaling pathways, 3) this combination is not predetermined, as previously believed, but is built step-by-step during postnatal development for certain synapses of a given neuron while other remains in a “default mode” (Paul, Sigoillot et al. 2023).
At the postsynaptic level, we have used synapse protein profiling strategy to identify the molecules present at the parallel fiber/Purkinje cell synapse (Selimi F. et al PloS biol 2009). We are now developing the same strategy for the climbing fiber/Purkinje cell synapse.
Role of postnatal activity in controlling the development of synapse identity
Activity might play a role in the development of synapse identity by controlling the molecular composition of synapses. Thus the interplay between activity and genetic factors could control synapse specification and be misregulated in some neurodevelopmental disorders.
We have shown that the postnatal administration of phencyclidine, a drug that is used to model schizophrenia in the mouse, can modify neuronal activity in the olivocerebellar system and leads to long-term changes in a subpopulation of climbing fiber/Purkinje cell synapses (Veleanu, Urrieta-Chavez, Sigoillot et al. 2022).
We are currently using various strategies to modulate activity during development in the olivocerebellar network and assess its role in synapse identity.
Synapses from invertebrates to vertebrates
Certain structural domains, such as CUB, Sushi (CCP), and TSP-1 protein domains, are found in synaptic proteins from invertebrates to vertebrates (González-Calvo et al. 2022).
We have identified Sushi domain containing protein 4 (SUSD4) as a new regulator of synaptic plasticity and motor coordination, and a NEDD4 binding partner (González-Calvo et al. 2021). SUSD4 mutations are associated with intellectual disabilities and autism spectrum disorders.