Obviously different NTs have different synaptic actions and it is of interest to see to what extent there are morphological correlates for these differing activities.
As mentioned previously, an axon generally makes either an axo-dendritic or axo-somatic synapse with another neuron. Gray (1959) has described subcellular features that distinguish these two main types of synapse. Under the electron microscope, his designated type I synaptic contact is like a disk (1-2 pm long) formed by specialised areas of opposed pre- and postsynaptic membranes around a cleft (300 A) but showing an asymmetric thickening through an accumulation of dense material adjacent to only the postsynaptic membrane. They are now often referred to as asymmetric synapses (Fig. 1.7). A type II junction is narrower (1 with a smaller cleft (200 A) and a more even (symmetric) but less marked membrane densification on both sides of the junction. In addition the presynaptic vesicles are generally large (300-600 A diameter), spherical and numerous at the asymmetric type I synapse but smaller (100-300 A), fewer in number and somewhat flattened or disk-like at the symmetric type II. Vesicles of varying shape can sometimes be found at both synapses, and while some differences are due to fixation problems, the two types of synapse described above are widely seen and generally accepted. They appear to be associated with fast synaptic events so that type I synapses are predominantly axo-dendritic, i.e. excitatory, and utilise glutamate while type II axo-somatic synapses are inhibitory generally utilising GABA, although the separation is not absolute. Asymmetric excitatory synapses outnumber GABA inhibitory symmetric synapses by up to 4:1, even though at such synapses there is usually only one actual synaptic junction whereas at the symmetrical inhibitory synapse there can be a number of such junctions—presumably to ensure adequate inhibitory control.
Unfortunately in routine EM (electron microscope) preparations one cannot identify the NT at individual synapses although structural features (shape of vesicle, asymmetric or symmetric specialisations) may provide a clue. At cholinergic synapses the terminals have clear vesicles (200-400 A) while monoamine terminals (especially NA) have distinct large (500-900 A) dense vesicles. Even larger vesicles are found in the terminals of some neuro-secretory cells (e.g. the neurohypophysis). One terminal can contain more than one type of vesicle and although all of them probably store NTs it is by no means certain that all are involved in their release.
Anatomical evidence can also be presented to support the concept of presynaptic inhibition and examples of one axon terminal in contact with another are well documented. These do not show the characteristics of either type I or II synapses but
Symmetric type II synapse
Figure 1.7 continued Different types of synaptic contact. (a) Symmetric and asymmetric synapses. The electromyograph from the anterior nuclear complex of the adult rat thalamus shows two terminals 1 and 2 establishing synaptic contact on the same dendrite. The electro-dense material in the dendrite is a HRP reaction product and identifies the dendrite as that of a thalamocortical projection neuron (the tracer-cholera toxin B conjugated to HRP was injected into the cingulate cortex). Terminal 1 makes a prominent Gray type I (asymmetric) and terminal 2 a Gray type II (symmetric) synaptic contact. The latter is also labelled with gold particles indicating that despite the spherical vesicles obtained in the fixation procedure, it contains GABA since the material was immunoreacted with antibody against GABA (post-embedding immunogold method). The picture was kindly provided by Professor A. R. Lieberman (University College London). Reproduced from Wang et al., Brain Res. Bull. 50: 63-76 (1999) published by Elsevier Science. (b) Schematic representation of asymmetric (Gray type I) and symmetric (Gray type II) synapses. Asymmetric synapses are 1-2 ^m long with a 30 nm (300 A) wide cleft and very pronounced postsynaptic density. Presynaptic vesicles are round (30 nm diameter). Symmetric synapses are shorter (1 ^m) with a narrower cleft (10-20 nm, 200 A) and although the postsynaptic density is less marked it is matched by a similar presynaptic one. The presynaptic vesicles are more disk-like (10-30 nm diameter)
the shape of the presynaptic vesicle is of particular interest because even if the net result of activating this synapse is inhibition, the initial event is depolarisation (excitation) of the axonal membrane. This might suggest that the vesicles should be spherical but since the NT is GABA, normally an inhibitory transmitter, the vesicles could be flattened. Thus, does the type of synapse or the NT and its function determine the shape of the vesicle? Generally the vesicles at these axo-axonic synapses are flattened (or disk-like) but some have spherical vesicles and so while the situation is not resolved vesicle shape tends to be linked with the NT they house.
In the lateral superior olive, antibody studies have shown four types of axon terminal with characteristic vesicles (Helfert et al. 1992). Those with round vesicles contain glutamate, those with flattened vesicles have glycine, while large plemorphic vesicles contain glycine and GABA and small plemorphic ones only GABA. Interestingly when GABA and glycine were found in the same terminals in the spinal cord, the post-synaptic membrane had receptors to both NTs.
Dendro-dendritic synapses have also been described which show characteristic synaptic connections and we need to abandon the belief that one neuron can only influence another through its axon terminals. Dendro-dendritic synapses can also be reciprocal, i.e. one dendrite can make synaptic contact with another and apparently be both pre- and postsynaptic to it.
If NTs can have distal non-synaptic effects then nerve terminals that do not make definite synaptic connections could be apparent. In smooth muscle the noradrenergic fibres ramify among and along the muscle fibres apparently releasing noradrenaline from swellings (varicosities) along their length rather than just at distinct terminals. These fibres are termed en passant axons (see Fig. 1.2). In the brain many aminergic terminals also originate from en passant fibres but it seems that not all of them form classical synaptic junctions.
Monoamines can also be found in terminals at both symmetric and asymmetric synapses, but this may be partly because they co-exist with the classical transmitters glutamate and GABA. The fact that vesicular and neuronal uptake transporters for the monoamines can be detected outside a synapse along with appropriate postsynaptic receptors does suggest, however, that some monoamine effects can occur distant from the synaptic junction (see Pickel, Nirenberg and Milner 1996, and Chapter 6).
For further details on the concept of synaptic transmission and the morphology of synapses see Shepherd and Erulkar (1997) and Peters and Palay (1996) respectively.
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