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

Abstract

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.

Stepwise molecular specification of excitatory synapse diversity on a target neuron

“…This would imply specific consequences on circuit development by environmental changes in terms of computation and symptom etiology. The facts that many human brain disease genes code for synaptic proteins, and that synapse diversity can be modulated by mutations relevant to neurodevelopmental disorders, highlight the importance of understanding the molecular rules generating synapse diversity during development 53,54 .…”

Alteration of synaptic protein composition during developmental synapse maturation

“…Paired box 6 (PAX6) is a member of the homeodomain transcription factor family that regulates the expression of many synaptic proteins and is involved in autism, intellectual disability and epilepsy. Synaptome analysis of PAX6 Het mice in postnatal development showed temporal changes in synapse density at the juvenile period (Tomas-Roca et al, 2022). Although synaptome analysis has mainly been performed with knock-in mice expressing synaptic scaffold proteins tagged with fluorescent molecules, this approach can be expanded by visualizing other major synaptic molecules.…”

“…Proteome analysis of biochemically prepared synaptic samples uses a mixture of synapses; therefore, it is impossible to distinguish individual differences in synaptic protein composition, such as in Figure 6b. Comprehensive analysis of individual synaptic puncta throughout the brain or ‘synaptome analysis’ describes the abundance of representative synaptic molecules (such as PSD‐95 and SAP102) in individual synapses throughout the brain (Bulovaite et al, 2022; Cizeron et al, 2020; Curran et al, 2020; Koukaroudi et al, 2023; Tomas‐Roca et al, 2022; Zhu, Cizeron, et al, 2018). This method evaluates synaptic protein composition, synaptic number and shape without loss of spatial information.…”

“…This study revealed multiple features of synaptic changes during development, including a rapid increase in synapse diversity during three postnatal weeks. The abnormality of synaptome in disease model animals has also been studied (Tomas‐Roca et al, 2022; Zhu, Cizeron, et al, 2018). In PSD‐93‐deficient mice, increased regional similarity of PSD‐95‐positive synapses was observed, whereas SAP102‐deficient mice showed decreased regional similarity (Zhu, Cizeron, et al, 2018).…”

Sleep maintains excitatory synapse diversity in the cortex and hippocampus

“…To better understand the role of sleep in regulating synapse protein composition and synapse number we have employed synaptome mapping technology to uncover the effects on SD on the mouse brain. Synaptome mapping enables highly systematic and large-scale analysis of the protein composition, protein lifetime and morphology of billions of individual synapses on a brain-wide scale [8][9][10][11] . This approach has revealed that excitatory synapses are highly diverse and can be categorised into different types and subtypes that together comprise the 'synaptome' of the brain 11 .…”