Abstract
Mapping the molecular composition of individual excitatory synapses across the mouse brain reveals high synapse diversity with each brain region showing a distinct composition of synapse types. As a first step towards systematic mapping of synapse diversity across the human brain, we have labelled and imaged synapses expressing the excitatory synapse protein PSD95 in twenty human brain regions, including 13 neocortical, two subcortical, one hippocampal, one cerebellar and three brainstem regions, in four phenotypically normal individuals. We quantified the number, size and intensity of individual synaptic puncta and compared their regional distributions. We found that each region showed a distinct signature of synaptic puncta parameters. Comparison of brain regions showed that cortical and hippocampal structures are similar, and distinct from those of cerebellum and brainstem. Comparison of synapse parameters from human and mouse brain revealed conservation of parameters, hierarchical organization of brain regions and network architecture. This work illustrates the feasibility of generating a systematic single-synapse resolution atlas of the human brain, a potentially significant resource in studies of brain health and disease.
Highlights
The vast majority of interactions between nerve cells occur at synapses
Using immunolabelling of PSD95 with high-resolution confocal microscopy and SYNMAP image analysis software, we have examined the distribution of excitatory synapses across 20 regions of the human brain in four individuals
We found that there are populations of PSD95-positive synaptic puncta with different sizes and intensities distributed in each brain region
Summary
The vast majority of interactions between nerve cells occur at synapses. The spatial location and the molecular composition of the pre- and postsynaptic elements are important factors in their cellular function. We recently systematically examined the distribution of PSD95 and SAP102 (another postsynaptic scaffold protein in excitatory synapses) at single-synapse resolution in hundreds of subregions within twelve main regions of the adult mouse brain (Zhu et al, 2018). Each brain region had a characteristic “signature” of PSD95-positive or SAP102-positive synapses, and synapses expressing both proteins had yet another map When these molecular types of synapses were further subcategorized using data on synapse size, shape and intensity of labelling, it was possible to build a larger catalogue and show that each synapse subtype had a unique synaptome map. Mutations in Dlg and Dlg, which cause intellectual disability and schizophrenia in humans, respectively, caused a change in the PSD95 synaptome architecture, suggesting that synaptic diseases manifest with altered spatial distribution of excitatory synapse types (Grant, 2019; Zhu et al, 2018). We discuss the utility of this data set for studies of the normal and diseased brain and the logistical considerations for large-scale human synaptome mapping
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