Structure of Synapses
We investigate structural and functional aspects of synaptic transmission and plasticity of synapses in the adult, developing and pathologically altered brain. Synapses are the key determinants for signal transduction in the brain.
Although they contain nearly the same structural subelements, an apposition zone including a pre- and postsynaptic density, a cleft and a pool of synaptic vesicles, it is the actual composition of these subelements that determines the behavior in synaptic transmission and plasticity of individual synapses embedded in different microcircuits of the brain. Using high-end electron microscopy and related techniques that allow subcellular and even molecular resolution it became possible to unravel and quantify those structural subelements providing important constrains that can be used for realistic numerical simulations of those parameters of synaptic transmission and plasticity that are still inaccessible to experiment.
Research on synaptic structures comes more and more into public focus given the steady increase in neurological and neurodegenerative disorders brought about by demographic changes. All these mental disease go along with massive structural changes at synapses, which ultimately lead to the overall dysfunction. This aspect represents one of our main focuses in the future.
The so-called Mossy Fiber Bouton in the stratum lucidum of the hippocampal CA3 subregion is a synapse involved in learning and memory processes and long-term potentiation. Three-dimensional computer-assisted reconstructions based on serial ultrathin sections throughout the entire Mossy Fiber Bouton - CA3 pyramidal cell synapse and subsequent digital electron micrographs alIow to generate a detailed model of its geometry. This model can then be used for numerical simulations of those parameters of synaptic transmission and plasticity that are still inaccessible to experiment and will finally lead to a better understanding of synaptic behaviour (see movie 1).
Cortical synapses, in contrast, are perfectly adapted to react to fast changes of signals from the sensory periphery as indicated by their different paired-pulse behaviour. Although synapses are composed of nearly the same structural elements, a direct comparison of the Mossy Fiber Bouton - CA3 pyramidal cell and cortical synapses shows that the size, density and distribution of active zones (transmitter release sites) and the organisation of the three functionally defined pools of synaptic vesicles differ substantially between the two and other CNS synapses. This may partially contribute and explain the differences in the functional behaviour of synapses embedded in different microcircuits of the brain (see movie 2).
Neurotransmitter receptors, at the molecular level, are key determinants in synaptic transmission and plasticity. Using "Freeze Fracture Replica" preparations combined with high-sensitive postimmunogold-labelling the density, distribution and possible co-localisation of AMPA- and NMDA-type glutamate receptors and their subunits can be detected and quantified resulting in so-called individual "receptor fingerprints". (see Figures 1-3).
Three-dimensional reconstruction of a hippocampal Mossy Fiber Bouton and its target structure. Sequence: Postsynaptic target dendrite, blue; active zones (Transmitter release sites), red; puncta adherens (Adhesions complexes), magenta; pool of synaptic vesicles, green; mitochondria, white; outline of the bouton, transparent yellow.
Three-dimensional reconstruction of two synapses terming on a dendritic segment of a layer 5 pyramidal cell. Sequence: Postsynaptic target dendrite, blue; active zones, red; pool of synaptic vesicles, green; mitochondria, white; outline of the boutons, transparent yellow.
Low power electron micrograph of the somatic region of a cortical layer 5 neurone and its surrounding neuropil of dendrites, synapses and glia processes taken from a "Freeze Fracture Replica" preparation
High power electron micrograph showing the density and distribution of AMPA-receptors (black gold particles, detected by a monoclonal panAMPA-antibody using the postimmunogold-technique, "Freeze Fracture Replica" preparation) at a postsynaptic density (PSD, red contour) of a cortical layer 5 synapse. The density and distribution of these receptors differed substantially between individual PSDs which may partially contribute and explain the differential functional behaviour between individual synapses in a given excitatory layer 5 pyramidal cell connection.
Density and distribution of the NR1 subunit of the NMDA receptor at a PSD (red contour) of a cortical layer 5 synapse. The strength, efficacy and synaptic plasticity critically depends on the distribution pattern of this receptor and the subunit composition.