Synapse diversity and synaptome architecture in human genetic disorders

Abstract

Over 130 brain diseases are caused by mutations that disrupt genes encoding the proteome of excitatory synapses. These include neurological and psychiatric disorders with early and late onset such as autism, schizophrenia and depression and many other rarer conditions. The proteome of synapses is highly complex with over 1000 conserved proteins which are differentially expressed generating a vast, potentially unlimited, number of synapse types. The diversity of synapses and their location in the brain are described by the synaptome. A recent study has mapped the synaptome across the mouse brain, revealing that synapse diversity is distributed into an anatomical architecture observed at scales from individual dendrites to the whole systems level. The synaptome architecture is built from the hierarchical expression and assembly of proteins into complexes and supercomplexes which are distributed into different synapses. Mutations in synapse proteins change the synaptome architecture leading to behavioral phenotypes. Mutations in the mechanisms regulating the hierarchical assembly of the synaptome, including transcription and proteostasis, may also change synapse diversity and synaptome architecture. The logic of synaptome hierarchical assembly provides a mechanistic framework that explains how diverse genetic disorders can converge on synapses in different brain circuits to produce behavioral phenotypes.

Figure 1

Synaptome mapping in mouse. Genes expressing synapse proteins are tagged in mice by fusing a genetically encoded fluorescent protein onto the C-terminus of postsynaptic scaffold proteins that assemble postsynaptic signaling complexes (PSD95, green; SAP102, magenta). These complexes are distributed into different synapse types that can be visualized with confocal microscopy. The synaptome map is built by quantification of synapse types from regions of the mouse brain. Example image of a coronal mouse brain section showing the differential distribution of PSD95 (green) and SAP102 (magenta). A synaptome map of a coronal section showing the dominant or major subtype from 37 subtypes in different regions. A synaptome map showing the extent of synapse diversity in different regions of the mouse brain. Figures adapted from Zhu et al., 2018 (31).

Figure 2

Synaptome hierarchical assembly. The diversity of synapse types and their spatial distribution in the synaptome arise from a hierarchical regulatory mechanism controlling gene and protein expression, assembly of proteins into complexes and supercomplexes and distribution of these supramolecular assemblies into synapses. Mutations acting on regulatory mechanisms at all levels of the hierarchy could influence synapse diversity and synaptome architecture.

Figure 3

Mutations reprogram synaptome architecture. Model of a normal synaptome comprised of 36 synapses made of three types assembled from two proteins (PSD95 and SAP102). Type 1 synapses express only PSD95, type 2 expresses only SAP102 and type 3 a mixture of both proteins. A mutation that knocks out PSD95 changes the synaptome architecture by abolishing type 1 synapses (empty circles in top two rows) and convert the type 3 synapses to type 2 synapses. A mutation that knocks out SAP102 does not affect type 1 synapses, but abolishes type 2 synapses and converts type 3 synapses into type 2 synapses.