Volume electron microscopy reveals 3D synaptic nanoarchitecture in postmortem human prefrontal cortex

Synaptic function is reflected in quantifiable ultrastructural features using electron microscopy (EM) approaches. This coupling of synaptic function and ultrastructure suggests that <i>in vivo</i> synaptic function can be inferred from EM analysis of <i>ex vivo</i> human brain tissue. To investigate this, we employed focused ion beam-scanning electron microscopy (FIB-SEM), a volume EM (VEM) approach, to generate ultrafine-resolution, three-dimensional (3D) micrographic datasets of postmortem human dorsolateral prefrontal cortex (DLPFC), a region with cytoarchitectonic characteristics distinct to human brain. Synaptic, sub-synaptic, and organelle measures were highly consistent with findings from experimental models that are free from antemortem or postmortem effects. Further, 3D neuropil reconstruction revealed a unique spiny dendritic shaft that exhibited several ultrastructural features characteristic of neuronal segments engaged in synaptic plasticity. Altogether, our findings provide critical proof-of-concept data demonstrating that <i>ex vivo</i> VEM analysis appears as an effective approach to infer <i>in vivo</i> synaptic functioning in human brain.