Pax6 Developmental Synaptome Atlas

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.

遗传性神经发育障碍会延缓正常功能的获得，并引发致残性表型。尽管如此，许多此类病症在幼儿期乃至青春期可出现症状自发缓解甚至完全改善，这提示大脑环路具备内在能力，可克服部分生殖系突变引发的功能缺陷。本研究以携带同源盒转录因子Pax6（homeobox transcription factor Pax6）突变的小鼠作为神经发育障碍模型，在小鼠从出生到成年的全脑范围内，对近万亿个兴奋性突触的分子组成进行了检测。Pax6单倍体不足在各个年龄段均未对突触总数量产生影响。与之相反，所有脑区中的兴奋性突触分子组成、出生后突触多样性的扩增以及正常突触组（synaptome）架构的获得均出现延迟，进而干扰认知功能相关网络及电生理模拟过程。两类关键发育年龄窗口中的特定兴奋性突触类型与亚型受到影响。这些表型在症状出现后的2-3周内即可得到逆转，使突触多样性与突触组架构恢复至正常发育轨迹。蛋白周转速率较快的突触亚型介导了突触组的重塑过程。这种全脑范围内重塑突触分子组成、以恢复并维持突触组架构发育轨迹的能力，或有助于增强遗传性神经发育障碍的耐受能力。