The Pax6 Developmental Synaptome Atlas

Pax6 is a member of the homeodomain transcription factor family and heterozygous (haploinsufficient) loss-of-function mutations cause autism, intellectual disability, epilepsy and aniridia (WAGR syndrome), which are phenocopied in Pax6^+/- mice. We examined the molecular composition of almost a trillion excitatory synapses on a brain-wide scale between birth and adulthood in in Pax6^+/- mice creating the Pax6 Developmental Synaptome Atlas. Pax6 haploinsufficiency had no impact on total synapse number at any age. By contrast, the postnatal expansion of synapse diversity and acquisition of normal synaptome architecture were delayed in all brain regions, interfering with network and cognitive functions. Specific excitatory synapse types and subtypes were affected in two key developmental age-windows. These phenotypes were reversed within 2-3 weeks of onset, restoring synaptome architecture to its normal developmental trajectory. Synapse subtypes with high rates of protein turnover mediated these events. These results show Pax6 regulates the synaptome architecture of the brain and that synaptome remodeling confers resilience to neurodevelopmental disorders.