Evidence For A Learninginduced Addition Of Synapses

Synapses are the primary link between neurons and have both presynaptic and postsynaptic components, separated by a small space called the synaptic cleft, all of which can be seen easily in osmium-fixed tissue at the electron microscopic level. The presynaptic component comprises a vesicle-filled axon terminal, with a small number of vesicles fused to or docked near the presynaptic membrane, and a very thin layer of electron-dense material immediately adjacent to the synaptic cleft. The postsynaptic component usually consists of an electron-dense plate called the PSD that is located on the cytosolic face of the postsynaptic membrane. The PSD is a protein-rich organelle containing neurotransmitter receptors, scaffolding molecules, actin-binding proteins, and a variety of other molecules involved in signal transduction. At the electron microscopic level, the PSD can be either approximately as thick as the presynaptic thickening, or it can be considerably thicker. The former type is a symmetric synapse involved in inhibitory synaptic transmission, whereas the latter is an asymmetric synapse mediating excitatory synaptic transmission. Most asymmetrical synapses in the brain are found on dendritic spines. A spine is a small protrusion that extends out from the parent dendrite and terminates as a head, which represents a postsynaptic element of a single excitatory synapse.

Axospinous excitatory synapses can be divided according to their PSD shape into perforated and nonperforated synaptic junctions9,10. When viewed in consecutive serial sections passing perpendicular or at an angle to the synaptic cleft, perforated synapses usually exhibit sectional PSD profiles showing a discontinuity or perforation that lacks the electron-dense material (Figure 23.1), hence the term "perforated." The PSD of perforated synapses can assume a fenestrated, horseshoe, or segmented shape. Serial sectioning of nonperforated synapses produces exclusively continuous PSD profiles, and the shape of a nonperforated PSD may be approximated by that of a flat circular or elliptical disc. Although a functional distinction between these two synaptic subtypes has not been

Perforated Synapses

Figure 23.1. Electron Micrographs of Consecutive Ultrathin Sections (A,B) through the Rat CA1 Stratum Radiatum Demonstrating Axospinous Synapses. Sectional profiles of postsynaptic densities (PSDs) are marked by arrowheads. Two small synapses between presynaptic axon terminals (labeled AT1 and AT2 in (A)) and postsynaptic dendritic spines (labeled SP1 and SP2 in (A)) display continuous PSD profiles (all of which are shown) and belong therefore to the nonperforated synaptic category. The large synapse formed by an axon terminal (labeled in AT3 in (A)) and dendritic spine (labeled SP3 in (A)) exhibits PSD profiles with discontinuities or perforations (arrows) and belongs therefore to the perforated synaptic category.

Figure 23.1. Electron Micrographs of Consecutive Ultrathin Sections (A,B) through the Rat CA1 Stratum Radiatum Demonstrating Axospinous Synapses. Sectional profiles of postsynaptic densities (PSDs) are marked by arrowheads. Two small synapses between presynaptic axon terminals (labeled AT1 and AT2 in (A)) and postsynaptic dendritic spines (labeled SP1 and SP2 in (A)) display continuous PSD profiles (all of which are shown) and belong therefore to the nonperforated synaptic category. The large synapse formed by an axon terminal (labeled in AT3 in (A)) and dendritic spine (labeled SP3 in (A)) exhibits PSD profiles with discontinuities or perforations (arrows) and belongs therefore to the perforated synaptic category.

shown directly, perforated synapses contain many more AMPA receptors (AMPARs) and NMDA receptors (NMDARs) than their nonperforated counterparts11,12 and are therefore likely to generate much larger unitary synaptic potentials.

Many electron microscopic studies of learning-related synaptic plasticity have taken advantage of the diverse morphology among synaptic subtypes. By necessity, however, electron microscopic studies are limited to a very small portion of brain tissue and thus have inherent technical limitations and biases, especially when examining possible loci of synaptic plasticity. Modern stereological techniques that have been designed to minimize such biases include the physical disector13 and systematic random sampling14. The physical disector is a three-dimensional stereological probe that consists of two adjacent ultrathin sections and has a volume limited by the sampling area and the thickness of the sampling section. This probe provides unbiased estimates of synaptic numerical density per unit volume by counting synapses present in one section (the sampling or reference section), but not in the other (the look-up section). Systematic random sampling is an unbiased method of choosing the area of tissue to be analyzed. The main advantage of systematic random sampling over other sampling schemes is that each area of tissue, along all three axes of the brain, has an equal probability of being chosen. Essentially, the first sampling field is chosen randomly, with subsequent sampling fields being systematically separated by a given distance throughout the extent of the brain region. Although this method requires multiple samples from each animal, the precision and accuracy afforded by this sampling technique is well worth the extra work14.

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