12/15/12 Ev ernote Web The Fine Structure of Synapses Saturday, December 15 2012, 12:12 PM The Fine Structure of Synapses Citation: Peters, A (2008) The Fine Structure of Synapses IBRO History of Neuroscience [http://www.ibro.info/Pub/Pub_Main_Display.asp?LC_Docs_ID=3313] Accessed: date Alan Peters The word “synapse” was coined by Sir Charles Sherrington in 1897 to denote the normal anatomical relations between contiguous neurons (see Foster and Sherrington, 1897). The origin of the word is explained in a footnote in Fulton’s Physiology of the Nervous System (Fulton, 1938, p. 55), and in the literature is it is quite clear that Sherrington recognized the synapse as a discontinuous intercellular junction. Although most scientists in the 1930s and afterwards accepted the neuron doctrine of Cajal, which postulates that each cell in the nervous system is a discrete entity that has no cytoplasmic continuity with other cells, it was not until synapses were examined by electron microscopists in the 1950s that the last doubt about the existence of cytoplasmic continuity between cells was laid to rest. In the 1950s it became evident that in both the invertebrate (Robertson, 1953) and vertebrate (Palade and Palay, 1954; Palay, 1956) nervous systems the pre- and postsynaptic elements of a synapse are separated by a cleft. It also became evident that the presynaptic elements contain vesicles, which were soon postulated to contain the chemicals released to allow conduction. From a morphological point of view, a chemical synapse can be described in term of its parts (Figure 1). https://www.ev ernote.com/edit/b5b0a889-9e26-4cc0-a678-ded644f 98de7#st=p&n=b5b0a889-9e26-4… 1/12 12/15/12 Ev ernote Web Figure 1: Asymmetric synapses (S1 and S2) between two axon terminals (At1 and At2), which contain spherical vesicles, and the smooth surfaced dendrite (Den) of a non-pyramidal cell in cerebral cortex. At the synaptic junctions the pre- and postsynaptic membranes are separated by a wide cleft and the postsynaptic membrane has a prominent dense coating on its cytoplasmic surface. Rat auditory cortex. x100, 000. The presynaptic component, which is most commonly an axon terminal, is characterized by its content of synaptic vesicles that often mingle with mitochondria; in the central nervous system the apposing postsynaptic element can have the features of any part of a neuron, and at a neuromuscular junction the postsynaptic component is a muscle cell (see Figure 2); the synaptic cleft is the intercellular space between the pre- and postsynaptic components and is usually between 20 and 30nm wide; the synaptic junction is formed by the plasma membranes of the pre- and postsynaptic components, the synaptic cleft, and the densities that occur both on the cytoplasmic faces of the pre- and postsynaptic components and within the synaptic cleft; at https://www.ev ernote.com/edit/b5b0a889-9e26-4cc0-a678-ded644f 98de7#st=p&n=b5b0a889-9e26-4… 2/12 12/15/12 Ev ernote Web some synaptic junctions vesicles accumulate against the presynaptic membrane at specific vesicles release sites, referred to as active zones (see Figure 2). https://www.ev ernote.com/edit/b5b0a889-9e26-4cc0-a678-ded644f 98de7#st=p&n=b5b0a889-9e26-4… 3/12 Figure 2: A motor end plate. Passing down the middle of the field is the basal lamina (B), which occupies the synaptic cleft separating the membranes of the axon terminal (At) and the striated muscle cell on the left. The axon terminal contains synaptic vesicles (sv) that are concentrated at the active zones (*) of the axolemma. Although no coated vesicles are evident in the axon terminal, the empty “shells” or “baskets” that form the coats of such vesicles are apparent in the axon terminal (arrowheads). Rat diaphragm. x 75,000. The following is a brief account of the different types of synapses found in the nervous system, with references to when some of the first descriptions of these synapses were made. Types of chemical synapses The study that had most influence on how chemical synapses are classified was that of Gray (1959). In tissue from cerebral cortex fixed by immersion in osmic acid, Gray (1959) encountered two types of synapses, which he called type I and type II. In his account he states that type I synapses, which involve dendritic spines and shafts, are formed by axon terminals that contain https://www.ev ernote.com/edit/b5b0a889-9e26-4cc0-a678-ded644f 98de7#st=p&n=b5b0a889-9e26-4… 4/12 12/15/12 Ev ernote Web round synaptic vesicles These synapses have a synaptic cleft that is abut 20nm wide and there is a prominent density on the cytoplasmic face of the postsynaptic membrane. Type II synapses on the other hand involve neuronal perikarya and dendritic shafts, have a narrower synaptic cleft of about 12nm, and a less prominent density beneath the postsynaptic membrane. In addition, the synaptic vesicles are smaller in the axon terminals forming type II synapses. Similar synapses have been found to occur in other parts of the central nervous system, and in the ventral cochlear nucleus Lenn and Reese (1966) found some axon terminals with synaptic vesicles having mean diameters of 45nm and other with mean diameters of 40nm. They deduced that terminals with the larger vesicles are excitatory and the others inhibitory in function. Over the years it has been shown that this deduction is correct. Asymmetric and symmetric synapses As in tissue fixed primarily in osmic acid, both the large and the smaller synaptic vesicles appear spherical in the freeze- fractures studies that were abundant in the 1970s (e.g. Akert et al., 1972; Sandri et al., 1977). However, the images of synapses changed when glutaraldehyde was introduced as a primary fixative (Sabatini et al., 1963). Prior to the advent of glutaraldehyde, preservation of central nervous system tissue was generally poor, but this changed in the late 1970s, when central nervous tissue began to be fixed by perfusion with mixtures of glutaraldehyde and formaldehyde, followed by osmication before embedding. This procedure greatly improved preservation, and while the vesicles within some terminals (Gray type I) retained their spherical shapes in glutaraldehyde fixed tissue, in other terminals some of the vesicles appear elongate (Gray type II). And studying cerebral cortex after glutaraldehyde fixation, Colonnier (1968) concluded that the two types of synapses described by Gray (1959) really represent the extremes of a continuum of morphology. Colonnier suggested that the two extremes should be referred to as asymmetric and symmetric synapses, on the basis of the prominence of the density on the cytoplasmic faces of the postsynaptic components. Asymmetric synapses are those with spherical synaptic vesicles and a prominent postsynaptic density, and in general such synapses are excitatory in function. Symmetric synapses lack a prominent postsynaptic density, and have pleomorphic vesicles, that is some vesicles have round profiles and others are elongate (Figures 3 and 4). Figure 3. Synapses in the cerebellum. In the upper half of the figure are two axon terminals (At1 and At2) from granule cells and they are making asymmetric synapses with the spines (sp1 and sp2) of Purkinje cells. In the spines are cisternae of smooth endoplasmic reticulum (SR). The synapses are surrounded by processes of astrocytes (As). The rest of the field is occupied by axons (Ax) of granule cells. Rhesus monkey. x60,000. In the lower half of the figure is a terminal (At) from a basket cell, and it is forming a symmetric synapse (arrow) with the perikaryon of a Purkinje cell (N). Note the neurofilaments (nf) and mitochondria (mit) in the axonal cytoplasm. Rhesus monkey. x35,000. In general asymmetric synapses are excitatory in function, and use transmitters such as glutamate and aspartate, although in some locations such as the spinal cord, substantia nigra, striatum and globus pallidus, superior colliculus and inferior olive, some asymmetric synapses are GABAergic (see lower Fig. 4, and Peters et al. 1991). Figure 4. Symmetric and asymmetric synapses. In the upper picture are two different axon terminals (At1 and At2) forming symmetric synaptic junctions (arrows) with the cell body (N) of pyramidal cell in cerebral cortex. The different packing densities and shapes of the synaptic vesicles in the two terminals suggest that they are from different types of presynaptic neurons. Note the punctum adhaerens (triangle) at one of the junctions. Cerebral cortex of rat. x80,000. In the lower picture is the axon terminal (At) of a basket cell in cerebellum. It is recognized by the presence of neurofilaments (nf) and pleomorphic vesicles (sv) in its cytoplasm. These inhibitory terminals are unusual in that they form asymmetric synapses with dendritic spines of Purkinje cells (sp1 and sp2). Rhesus monkey. x50,000. https://www.ev ernote.com/edit/b5b0a889-9e26-4cc0-a678-ded644f 98de7#st=p&n=b5b0a889-9e26-4… 5/12 12/15/12 Ev ernote Web In general, however, symmetric synapses are inhibitory in function. Attempts have been made to fit synapses in all parts of the nervous system into these two basic categories, and while there has been some success, a number of variations have been encountered, even in cerebral cortex in which Peters and Harriman (1990) distinguished at least three types of axon terminals forming symmetric synapses. Nevertheless, this number pales in the light of studies on spinal cord, in which Bodian (1972; 1975), Conradi (1969) and McLaughlin (1972) have described as many as six types of axon terminals that can be distinguished from each other on the sizes and shapes of their synaptic vesicles. An example of the kinds of variation that can occur is shown in Figure 5, which is from the cochlear nucleus. Figure 5.