Developmental disruption and restoration of brain synaptome architecture in the murine Pax6 neurodevelopmental disease model

Neurodevelopmental disorders of genetic origin delay the acquisition of normal abilities and cause disabling phenotypes. Nevertheless, spontaneous attenuation and even complete amelioration of symptoms in early childhood and adolescence can occur in many disorders, suggesting that brain circuits possess an intrinsic capacity to overcome the deficits arising from some germline mutations. We examined the molecular composition of almost a trillion excitatory synapses on a brain-wide scale between birth and adulthood in mice carrying a mutation in the homeobox transcription factor Pax6, a neurodevelopmental disorder model. Pax6 haploinsufficiency had no impact on total synapse number at any age. By contrast, the molecular composition of excitatory synapses, the postnatal expansion of synapse diversity and the acquisition of normal synaptome architecture were delayed in all brain regions, interfering with networks and electrophysiological simulations of 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 synapse diversity and synaptome architecture to the normal developmental trajectory. Synapse subtypes with rapid protein turnover mediated the synaptome remodeling. This brain-wide capacity for remodeling of synapse molecular composition to recover and maintain the developmental trajectory of synaptome architecture may help confer resilience to neurodevelopmental genetic disorders.

Description: Subtype classification in different brain subregions at P1.
2 Column A represents the 131 brain subregions, the first row corresponds to the mouse ID number and the third row the number of the subtype. Subtype classification values in different brain subregions as defined in the Developing Allen Reference Atlas at P1.
File Name: Supplementary Data 6. Description: Subtype classification in different brain subregions at P7.
Column A represents the 131 brain subregions, the first row corresponds to the mouse ID number and the third row the number of the subtype. Subtype classification values in different brain subregions as defined in the Developing Allen Reference Atlas at P7.
File Name: Supplementary Data 7.
Description: Subtype classification in different brain subregions at P14.
Column A represents the 131 brain subregions, the first row corresponds to the mouse ID number and the third row the number of the subtype. Subtype classification values in different brain subregions as defined in the Developing Allen Reference Atlas at P14. Each spreadsheet contains subtype classification data from each subtype (1-37).
File Name: Supplementary Data 8. Description: Subtype classification in different brain subregions at P21.
Column A represents the 131 brain subregions, the first row corresponds to the mouse ID number and the third row the number of the subtype. Subtype classification values in different brain subregions as defined in the Developing Allen Reference Atlas at P21. Each spreadsheet contains subtype classification data from each subtype (1-37).
File Name: Supplementary Data 9.
Description: Subtype classification in different brain subregions at P28.
Column A represents the 131 brain subregions, the first row corresponds to the mouse ID number and the third row the number of the subtype. Subtype classification values 3 in different brain subregions as defined in the Developing Allen Reference Atlas at P28. Each spreadsheet contains subtype classification data from each subtype (1-37).
File Name: Supplementary Data 10. Description: Subtype classification in different brain subregions at P35.
Column A represents the 131 brain subregions, the first row corresponds to the mouse ID number and the third row the number of the subtype. Subtype classification values in different brain subregions as defined in the Developing Allen Reference Atlas at P35. Each spreadsheet contains subtype classification data from each subtype (1-37).
File Name: Supplementary Data 11. Description: Subtype classification in different brain subregions at P42.
Column A represents the 131 brain subregions, the first row corresponds to the mouse ID number and the third row the number of the subtype. Subtype classification values in different brain subregions as defined in the Developing Allen Reference Atlas at P42. Each spreadsheet contains subtype classification data from each subtype (1-37).
File Name: Supplementary Data 12.
Description: Subtype classification in different brain subregions at P49.
Column A represents the 131 brain subregions, the first row corresponds to the mouse ID number and the third row the number of the subtype. Subtype classification values in different brain subregions as defined in the Developing Allen Reference Atlas at P49. Each spreadsheet contains subtype classification data from each subtype (1-37).
Abbreviations, see Supplementary Data 1. Description: Synapse subtype phenotypes in the neocortex of Pax6 +/mice. Column A, time points (P7, P14, P21, P35, P42) with significant differences; column B, neocortical areas as defined in the Developing Allen Reference Atlas at P56.