Structure activity relationship of synaptic and junctional neurotransmission

Abstract

Chemical neurotransmission may include transmission to local or remote sites. Locally, contact between 'bare' portions of the bulbous nerve terminal termed a varicosity and the effector cell may be in the form of either synapse or non-synaptic contact. Traditionally, all local transmissions between nerves and effector cells are considered synaptic in nature. This is particularly true for communication between neurons. However, communication between nerves and other effectors such as smooth muscles has been described as nonsynaptic or junctional in nature. Nonsynaptic neurotransmission is now also increasingly recognized in the CNS. This review focuses on the relationship between structure and function that orchestrate synaptic and junctional neurotransmissions. A synapse is a specialized focal contact between the presynaptic active zone capable of ultrafast release of soluble transmitters and the postsynaptic density that cluster ionotropic receptors. The presynaptic and the postsynaptic areas are separated by the 'closed' synaptic cavity. The physiological hallmark of the synapse is ultrafast postsynaptic potentials lasting milliseconds. In contrast, junctions are juxtapositions of nerve terminals and the effector cells without clear synaptic specializations and the junctional space is 'open' to the extracellular space. Based on the nature of the transmitters, postjunctional receptors and their separation from the release sites, the junctions can be divided into 'close' and 'wide' junctions. Functionally, the 'close' and the 'wide' junctions can be distinguished by postjunctional potentials lasting ~1s and tens of seconds, respectively. Both synaptic and junctional communications are common between neurons; however, junctional transmission is the rule at many neuro-non-neural effectors.

Figure 1

Flow diagram of different modes of neurotransmission.

Figure 2

Nitrergic varicosities in circular smooth muscle strip of the mouse gastric fundus. Top panel shows calcium fluorescence in the varicosities. Note that the nerve varicosities are visible as beaded structures lying along the bed of smooth muscle cells (thin arrows). The inter-varicosity axons are also clearly visible, giving a beads-on-string appearance (thick arrows). Middle panel shows DAF fluorescence indicating nitric oxide production. Note that the nerve varicosities (green) are appear as beaded structures, similar to those seen by calcium fluorescence. Bottom panel shows profiling of DAF signals. Note small signals in the basal state, intense signals after EFS and loss of signals after pretreatment with L-NAME, indicating their nitrergic nature. The fluorescence images were obtained using multiphoton microscope in muscle strips preloaded with calcium orange and DAF-2DA. EFS was applied under nonadrenergic noncholinergic conditions (From (Thatte et al., 2009), by permission).

Figure 3

Ultrastructure of nerve varicosities containing different types of vesicles and their relationship to synaptic specialization in the CNS neurons. (A) Shows a varicosity loaded with SCV many of which are in close association with the varicosity membrane at presynaptic membrane specialization (large arrow). The apposing postsynaptic membrane possesses postsynaptic density. This synapse is on a dendrite in superior olive, X 60.000 (From (Heuser JE, 1977), with permission). The specialized active zone is for active synaptic exocytosis. (B) Shows a varicosity with DCV of various sizes. Specialized presynaptic zone with docked vesicles are not found in such varicosities. This illustration represents an adrenergic varicosity in rat vas deferens, X 110,000; (From (Basbaum, 1974), with permission). (C) shows a varicosity containing SCV and LDCV. Note that the synaptic junction is characterized by some widening of cleft and pre- and post-synaptic plaques. Also note an interesting distribution of the vesicles in the varicosity: whereas SCV are clustered around the presynaptic specialization, the LDCV are seen away from the synapse, X77000; From dentate nucleus of cerebellum of Macaca mullata (From (Palay S.L., 1977), with permission).

Figure 4

Three time courses of postsynaptic potentials in enteric neurons. (A) Shows fast excitatory postsynaptic potential (fEPSP) with duration of ~50ms. (B) Shows intermediate postsynaptic potentials (IPSP) having duration of ~600 ms; B1) Shows intermediate excitatory postsynaptic potential (iEPSP) and B2) Shows inhibitory postsynaptic potential (iIPSP). The iIPSP shown here was elicited by a train of stimuli; however, a single pulse also produces a similar IPSP. (C) Shows slow post synaptic potential (sPSP) with a duration of >12,000 ms. C1) shows sEPSP elicited by a single pulse and C2) shows a sEPSP elicited by a train of stimuli. Note long duration of this sEPSP. Thus durations of intermediate potentials are 20-times longer and that of sEPSPs is >400-times longer than that of the fEPSP. The time course of iIPSP and sIPSP are similar to those of fastJP and slowJP respectively (From (Monro et al., 2004), with permission).

Figure 5

The presynaptic active zone (A) and (B) are electron micrographs of cat spinal cord synapse cut perpendicularly (A) and tangentially (B), respectively. Note the regularly arranged dense projections in the presynaptic active zone. The electron density of the grid was enhanced by the use of 1% phosphotungstic acid. Vesicle membranes were not preserved by the fixative; Scale bar 100nm (From (Gray, 1963), with permission).

Figure 6

The presynaptic active zone and the synaptic grid (A) is a 3D reconstruction of transverse section through a varicosity Note that active zone with docked vesicles at the varicosity membrane (blue) forms a small localized zone of the varicosity membrane (From (Siksou et al., 2007), with permission). (B) Represents a model of the presynaptic grid. Fibrillar components originating at the presynaptic membrane project into the cytoplasm. The presynaptic particles with spaces in between are present next to the membrane. (C) Three-dimensional model of the presynaptic grid formed by the particles. The particles form a hexagonal array with sieve like formation. The particle grid supports selective access of small vesicles to the plasma membrane for their subsequent fusion The particles are linked to PSD of the postsynaptic cell across the synaptic cleft by adhesion molecules. Presynaptic particles also contain components necessary for the retrieval of vesicle membrane proteins after their fusion with the plasma membrane. (From (Phillips et al., 2001), with permission).

Figure 7

Molecular anatomy of the presynaptic active zone. Three distinct complexes help to define the active zone (described in text). The first complex is largely structural, and is thought to hold the active zone in register with the postsynaptic density (PSD) and clusters calcium channels within the active plasma membrane. The second complex is involved in synaptic vesicle docking and fusion. The third complex is involved in synaptic vesicle endocytosis. (From (Qui, 2004), with permission).

Figure 8

Schematic diagram of key steps involved in exocytosis of vesicles at the active zone. For details, refer text. (Modified from (Tang et al., 2006) and (Sudhof, 2008b), with permission).

Figure 9

Recycling of the synaptic vesicle. For details, refer text (From (Lang et al., 2008), with permission).

Figure 10

Schematic illustration of synaptic cleft Synaptic cleft separates the presynaptic active zone with SCV docked on the varicosity membrane and synaptic grid and the postsynaptic density. Note that the synaptic cleft may be wider (20–30nm) than the adjoining nonsynaptic, junctional space (10–20nm). However, width of the junctional space is highly variable (From De Camilli P, 2003, with permission).

Figure 11

Molecular anatomy of the postsynaptic density For details, refer text (From Feng et al., 2009, with permission).

Figure 12

Distribution of vesicles around synaptic specialization in enteric varicosities. (A) Shows a varicosity containing SCV and presynaptic active zone with prominent cytoplasmic projections. Also note the associated postsynaptic density on a dendrite. (From myenteric plexus of the guinea pig ileum) Marker: 0.5 µm. (B) Shows a varicosity containing SGV contacting with an intramural neuron. Note the absence of well-defined synapse. Marker 0.2 µm (From myenteric plexus of the guinea pig ileum). (C) Shows a nerve varicosity with different types of synaptic vesicles. Note that SCV are clustered around an area of active zone and the SCV seem to be interposed between the DCV and the active zone. Marker: 0.5 µm (From submucosal enteric plexus of the guinea pig ileum). Note that the distribution of the vesicles in enteric varicosities is similar to that in the CNS varicosities (From (Gabella, 1979), with permission).

Figure 13

Pharmacological identification of chemical nature of the fast EPSP in S neurons the myenteric plexus of guinea pig ileum. (A) An exclusive cholinergic fEPSP that is blocked by hexamethonium. (B) A mixed cholinergic and purinergic fEPSP that is blocked only be a combination of hexamethonium and ionotropic P2X receptor antagonist, PPADS (C) A mixed cholinergic and serotonergic fEPSP that is only blocked by a combination of hexamethonium and ondansetron. The percentages of synaptic responses of each type are indicated. (From Galligan, 2002a, with permission).

Figure 14

Close contacts between nerve varicosities and ICC and smooth muscle cell in the gut. (A) Shows a varicosity containing SCV and some LDCV. This varicosity makes a close ~20nm contact with a thin process of ICC and end of a smooth muscle cell. Also note membrane densities on the presynaptic membrane but no postsynaptic specialization. The section in a single plane section gives the illusion that the thin processes of ICC form a barrier between the varicosity and the smooth muscle cell that is seen several hundred nm away (scale, 0.5µ) (B) Shows 10–20nm close contact between a circular muscle and a varicosity filled with SCV The presynaptic electron-dense lining is indicated by an arrow, X41,000. (C) Shows close contact 10–20nm between a longitudinal muscle cell and two axon terminals: one containing a mixture of SCV and LDCV and the other containing only LDCV. Electron dense lining is marked by an arrow, X28,000 (A is from Rumessen et al., 1982, with permission; B and C are from Mitsui et al., 2002, with permission).