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Synapses are specialised contacts between neurons. At postsynaptic terminals of glutamatergic synapses, protein complexes process and transmit the information received from the presynaptic terminal. Scaffolding proteins, among which members of the disc large homologue (DLG) family are the most abundant, assemble the molecular machinery in the postsynaptic terminal. Recently, two members of the DLG family, postsynaptic density protein 95 (PSD95) and synapse associated protein 102 (SAP102), have been shown to form different types of complexes, thus giving the synapse different signalling capabilities. However, the spatial distribution of these synaptic markers in different synapses remains elusive due to technical challenges. This thesis presents the first applications of a new method, the Genes to Cognition Synaptome Mapping pipeline (G2CSynMapp), to map individual synapses at the whole-brain level, in a quantitative and unbiased manner. This method was used to generate PSD95 and SAP102 synaptome maps – i.e. comprehensive maps of PSD95 and SAP102 positive synapses – in the mouse brain and to achieve three aims: i) characterise PSD95 and SAP102 synapse diversity, ii) measure the trajectory of PSD95 and SAP102 synapse changes during the postnatal lifespan and iii) determine whether PSD95 synaptome is reorganised by mutation. First, I have used G2CSynMapp to generate the first synaptome maps in the adult mouse brain. This reference map of PSD95 and SAP102 positive synapses revealed a highly organised distribution pattern of glutamatergic synapses between anatomical regions. Moreover, it uncovered that synapse populations are very diverse within anatomical regions and can form patches, gradients and input-specific glomeruli. Second, the trajectories of PSD95 and SAP102 synaptomes were mapped across the mouse postnatal lifespan. At birth, synapse densities are low and increase rapidly during the first month of life. During ageing, the density of SAP102 and PSD95 positive synapses decrease gradually. Interestingly, different anatomical regions show different trajectories of synapse density and parameters across the lifespan. Moreover, the packing of PSD95 and SAP102 at synapses have specific pattern of changes. Third, the PSD95 synaptome was found to be reorganised differently in two disease models, PSD93 and SAP102 knock-out mice. In humans, mutations in the genes encoding PSD93 or SAP102 have been involved in schizophrenia and mental retardation, respectively. Of particular interest, opposite changes were identified in the neocortex of the two mutant lines that are reminiscent of their inverse behavioural phenotypes.

Terminal selectors are transcription factors that control neuronal identity by regulating the expression of key effector molecules, such as neurotransmitter (NT) biosynthesis proteins, ion channels and neuropeptides. Whether and how terminal selectors control neuronal connectivity is poorly understood. Here, we report that UNC-30 (PITX2/3), the terminal selector of GABA motor neuron identity in , is required for NT receptor clustering, a hallmark of postsynaptic differentiation. Animals lacking or the short isoform of the MN-secreted synapse organizer ( ), display severe GABA receptor type A (GABA R) clustering defects in postsynaptic muscle cells. Mechanistically, UNC-30 acts directly to induce and maintain transcription of and GABA biosynthesis genes (e.g., , ). Hence, UNC-30 controls GABA R clustering on postsynaptic muscle cells and GABA biosynthesis in presynaptic cells, transcriptionally coordinating two critical processes for GABA neurotransmission. Further, we uncover multiple target genes and a dual role for UNC-30 both as an activator and repressor of gene transcription. Our findings on UNC-30 function may contribute to our molecular understanding of human conditions, such as Axenfeld-Rieger syndrome, caused by PITX2 and PITX3 gene mutations.

The precise localization of postsynaptic receptors opposite neurotransmitter release sites is essential for synaptic function. This alignment relies on adhesion molecules, intracellular scaffolds, and a growing class of extracellular scaffolding proteins. However, how these secreted proteins are retained at synapses remains unclear. We addressed this question using C. elegans neuromuscular junctions, where Punctin, a conserved extracellular synaptic organizer, positions postsynaptic receptors. We identified CLE-1, the ortholog of collagens XV/XVIII, as a key stabilizer of Punctin. Punctin and CLE-1B, the main isoform present at neuromuscular junctions, form a complex and rely on each other for synaptic localization. Punctin undergoes cleavage, and in the absence of CLE-1, specific fragments are lost, resulting in the mislocalization of cholinergic receptors to GABAergic synapses. Additionally, CLE-1 regulates receptor levels independently of Punctin. These findings highlight a crucial extracellular complex that maintains synapse identity.

How synapses change molecularly during the lifespan and across all brain circuits is unknown. We analyzed the protein composition of billions of individual synapses from birth to old age on a brain-wide scale in the mouse, revealing a program of changes in the lifespan synaptome architecture spanning individual dendrites to the systems level. Three major phases were uncovered, corresponding to human childhood, adulthood and old age. An arching trajectory of synaptome architecture drives the differentiation and specialization of brain regions to a peak in young adults before dedifferentiation returns the brain to a juvenile state. This trajectory underscores changing network organization and hippocampal physiology that may account for lifespan transitions in intellectual ability and memory, and the onset of behavioral disorders. Footnotes * https://www.brain-synaptome.org * https://doi.org/10.7488/ds/2711

C. elegans, is absolutely required for the synaptic clustering of homomeric α7-like N-acetylcholine receptors (AChR) and regulates the synaptic content of heteromeric L-AChRs. SDN-1 is concentrated at neuromuscular junctions (NMJs) by the neurally-secreted synaptic organizer Ce-Punctin/MADD-4, which also activates the transmembrane netrin receptor DCC. Those cooperatively recruit the FARP and CASK orthologues that localize N-AChRs at cholinergic NMJs through physical interactions. Therefore, SDN-1 stands at the core of the cholinergic synapse organization by bridging the extracellular synaptic determinants to the intracellular synaptic scaffold that controls the postsynaptic receptor content. Competing Interest Statement The authors have declared no competing interest. Footnotes * ↵c Co-first authors