Synapses in the brains of mammalian animals have been extensively studied in the past. In contrast, the structural composition of human synapses is, to date, much less investigated. What do we know at this point?
By Astrid Rollenhagen and Joachim H.R. Lübke
Synapses are key elements in the communication between neurons (nerve cells) in the brain. Although they all are composed of nearly the same structural sub-elements, their “behaviour” critically depends on the network in which they are integrated. Their individual structural composition determines the properties of individual synaptic connections, and thus the computations of the entire network.
Two structural sub-elements of a synapse are particularly important in that regard: on the one hand, the so-called active zones, i.e. the structural equivalent of the functional neurotransmitter release sites, and on the other hand synaptic vesicles, which can be separated into three functional groups – the readily releasable, the recycling and the resting pool. The number, size and shape of active zones as well as the size and organisation of synaptic vesicles in those pools are crucial factors in governing the “behaviour” of synaptic complexes within a given brain network.
Researchers have been pondering the question for a long time on whether experimental findings about synapses in experimental animals can actually be transferred one-on-one to the human brain.
In the late last century, neuroscientists started to generate quantitative 3D models of synapses in experimental animals. They considered this to be one possible way to correlate structure with function, thus allowing reliable predictions about the synapses’ computational properties.
Furthermore, the “re-introduction” of electron microscopy (EM) – achieved by modern high-end, high-resolution transmission-EM (Figure 1), focused ion beam scanning-EM, and EM-tomography (Video 1) – has enormously improved our knowledge about the brain’s synaptic organization in various animal species. It also allowed new insights into the “microcosms” of the human brain in health and disease.
Preliminary results in the human temporal lobe neocortex using biopsy samples taken during epilepsy surgery showed that synaptic boutons in humans differ substantially in several structural parameters from experimental animals, such as the size and shape of active zones and the organization of the three pools of synaptic vesicles.
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Figure 1: Upper panel: Electron micrograph of a single image taken from a series of 100 ultrathin sections showing a mushroom spine emerging from a dendritic segment (transparent blue) and a terminating synaptic bouton (transparent yellow) in layer 6 of the human temporal lobe neocortex. The active zone is highlighted in red, mitochondria in transparent white and synaptic vesicles in green. Scale bar: 0.5 µm; Lower panel: 3D-volume reconstruction of the synaptic complex shown above. Same colour code as above. Here, the outline of the synaptic bouton was omitted to better visualize mitochondria, the large perforated, ring-like active zone (surface area: 0.80 µm2, volume: 0.013 µm3, see also inset) and the pool of synaptic vesicles (N=2070 in this synaptic bouton). Scale bar 0.5 µm. © Mrs. cand. med. Sandra Schmuhl-Giesen, PhD student in the Group: “Structure of Synapses”, INM-10, Research Centre Jülich GmbH, Germany.
Video 1: EM tomography of three synaptic complexes, composed of dendritic spines and synaptic boutons, in layer 1 of the human temporal lobe neocortex. By tilting the ultrathin section from -60o to +60o this technique allows a walk along the active zone and thus the identification of so-called ‘docked’ vesicles. Scale bar 0.2 µm. © Bernd Walkenfort and Dr. Mike Hasenberg, Medical Research Centre, IMCES Electron Microscopy Unit (EMU), University Hospital Essen, Germany.
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