Functional complexomics associated with maturation and activity-dependent plasticity of excitatory synapse

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Processing and storage of information in the brain fundamentally rely on proper signal transduction and activity-dependent dynamics in excitatory synapses. Key players in these synapses are AMPA-type glutamate receptors (AMPARs), macro-molecular complexes that drive almost any aspect of synapse physiology from synaptogenesis to electrical signal transduction and synaptic plasticity underlying memory formation and learning. We have recently uncovered biogenesis of AMPARs in the ER as a ‘multi-state assembly line’ and found that its impairment/disruption leads to severe consequences in both humans and rodents. In humans loss-of-function mutations in protein FRRS1l, a key determinant of the AMPAR assembly process, lead to severe forms of intellectual disability with strongest impairment in memory formation, motor skills and cognition. In mice, knock-out of FRRS1l abolished activity-dependent synaptic plasticity, reduced synapse formation and maturation and profoundly impaired learning. Interestingly, virally-driven re-expression of FRRS1l fully reversed all knock-out induced phenotypes and thus provided an experimental tool for ‘switching on’ formation of synapses and plastic behavior at will. In this project, we will use these latest insights for a first-time unbiased and comprehensive investigation of proteins that are required for building functional synapses with activity-driven plasticity. For this purpose we will (i) perform quantitative proteomic analyses on defined brain regions from FRRS1l knock-out mice before and after switching on AMPAR biogenesis by stereotactically delivered viruses, (ii) investigate identified key proteins and protein complexes for their subcellular distribution and dynamics and (iii) study their functional significance and characteristics in-vitro and in-vivo. Together, these analyses will decipher the molecular processes driving formation of excitatory synapses and their activity-dependent plasticity.