Synapse identity and complexity in the mammalian brain
The goal of our team is to understand the molecular mechanisms that control the development of a functional brain. Answering this fundamental question will also help increase our knowledge of the mechanisms that could be deficient in neurodevelopmental disorders such as autism or schizophrenia.
The brain is composed of many different types of neuronal populations that form functional networks by establishing specific synapses. Indeed, synapses are complex macromolecular structures with different morphological and functional characteristics, depending on the types of neurons that they connect. Our team's aim is to identify the molecular determinants of synapse diversity and understand how these determinants contribute to normal network formation in the mammalian brain.
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 (PCs), the sole output of the cerebellar cortex, receive two types of excitatory inputs, one from the granule cells through the parallel fibers (PF), and one from the inferior olivary neurons, through the climbing fibers (CF). These two types of excitatory synapses have clear differences in terms of their physiology and form on separate dendritic territories on Purkinje cells.
Our model: diversity of excitatory synapses in cerebellar Purkinje cells.
The C1QL1/BAI3 complex
The adhesion-G protein coupled receptor Brain Angiogenesis Inhibitor 3 (BAI3) was identified by our group in biochemical fractions of parallel fiber/Purkinje cell postsynaptic densities using the synapse protein profiling strategy (Selimi F. et al. PloS Biol 2009). Our functional analysis showed a role for this receptor in controlling both dendritogenesis and excitatory synaptogenesis in cerebellar Purkinje cells (Lanoue et al. Mol Psy 2013; Sigoillot et al. Cell rep 2015).
C1QL1, a secreted protein that belongs to the complement C1Q related family, is a ligand for BAI3. Data obtained by our group showed that C1QL1 is one of the most highly and specific gene for inferior olivary neurons giving rise to climbing fibers. We also showed that iis specific expression by inferior olivary neurons is necessary for CF synaptogenesis on Purkinje cells (SIgoillot et al. Cell rep 2015).
Thus the C1QL1/BAI3 complex is one of the molecular determinants of the identity of Climbing fiber/Purkinje cell synapses. We are further analyzing the role of this complex during development of the olivo-cerebellar network and in the etiology of psychiatric disorders, since defects in the BAI3 have been associated with some psychiatric symptoms.
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.
At the postsynaptic level, we have used synapse protein profiling strategy to identify the moleculaes 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.
Our goal is to perform the first comparison of the composition of two excitatory synapses established on the same target-neuron: the parallel fiber/Purkinje cell synapse and the climbing fiber/Purkinje cell synapse.
This project is supported by an ERC consolidator grant.