Abstract
Modern electron microscopy (EM) such as fine-scale transmission EM, focused ion beam scanning EM, and EM tomography have enormously improved our knowledge about the synaptic organization of the normal, developmental, and pathologically altered brain. In contrast to various animal species, comparably little is known about these structures in the human brain. Non-epileptic neocortical access tissue from epilepsy surgery was used to generate quantitative 3D models of synapses. Beside the overall geometry, the number, size, and shape of active zones and of the three functionally defined pools of synaptic vesicles representing morphological correlates for synaptic transmission and plasticity were quantified. EM tomography further allowed new insights in the morphological organization and size of the functionally defined readily releasable pool. Beside similarities, human synaptic boutons, although comparably small (approximately 5 µm), differed substantially in several structural parameters, such as the shape and size of active zones, which were on average 2 to 3-fold larger than in experimental animals. The total pool of synaptic vesicles exceeded that in experimental animals by approximately 2 to 3-fold, in particular the readily releasable and recycling pool by approximately 2 to 5-fold, although these pools seemed to be layer-specifically organized. Taken together, synaptic boutons in the human temporal lobe neocortex represent unique entities perfectly adapted to the “job” they have to fulfill in the circuitry in which they are embedded. Furthermore, the quantitative 3D models of synaptic boutons are useful to explain and even predict the functional properties of synaptic connections in the human neocortex.
Highlights
One major and important question in synaptic neuroscience is whether findings about the structural compositions of the adult, developmental, and pathologically altered brain in experimental animals can be transferred one to one to the human brain
In the beginning of the presented work, we evaluated if in our hands, transmission EM (TEM) or (FIB-) SEM represented the best-suited imaging modality to characterize the organization of the neuropil and its components throughout the different layers and temporal gyri in highest detail
We found that both methods were able to visualize key ultrastructural sub-elements of the investigated tissue, but with our so far established and refined sample preparation and image acquisition protocols, the contrast in the resulting focused ion beam scanning EM (FIB-SEM) images was clearly poorer compared to corresponding TEM images
Summary
One major and important question in synaptic neuroscience is whether findings about the structural compositions of the adult, developmental, and pathologically altered brain in experimental animals can be transferred one to one to the human brain. This can be partially attributed to the non-availability of ultrastructural well-preserved human tissue samples that allow investigations at the fine-scale high-resolution cellular and subcellular electron microscopy (EM) level. Structural investigations at the cellular and subcellular EM level are limited by the poor ultrastructural preservation of tissue samples obtained from post-mortem brains This can be mainly attributed to hypoxia-mediated autolysis within the long time window between the decease of the patient and the removal of the brain by the pathologist
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