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Cell identification and reproducibility Each of the 40 neurons
of the C. elegans posterior nervous system has a reproducible
set of features by which it can be unambiguously identified in
different individuals. These features include cell body position,
number and direction of fiber projections, and size and cytoplasmic appearance of the fibers. For each of the different sorts of features, the degree of reproducibility between isogenic individuals appears to be as good as that bilaterally within a given
individual. Table 2 provides a summary list of some of the most
salient features and a correspondence of naming systems between previous
There is a remarkable economy of cell number, cell shape, and synaptic arrangements. The number of neurons serving any particular function is very small. Neurons with combined functions occur, and there are few layers of interneurons interposed between sensory cells and motor cells. Each neuron lacks secondary branches within the tail region; the anterior nervous system is fairly similar in this respect. The absolute number of synaptic contacts per neuron or per synapse class is certainly not large, even compared to most invertebrates. This limited set of reproducible neurons with distinct functional roles offers unique opportunities for physical manipulation of the nervous system, by laser ablation or by genetic or pharmacological means.
Cell function: sensory reception and processing. A principal function of the C. elegans posterior nervous system appears to be the reception and processing of information from posterior sensory receptors. Previous behavioral and genetic studies have shown that C. elegans is able to distinguish chemical stimuli (Ward, 1973; Dusenbery et al., 1975), mechanical stimuli (Chalfie and Sulston, 1981), optical stimuli (Burr, 1985), osmotic gradients (Culotti and Russell, 1978), and thermal gradients (Hedgecock and Russell, 1975). Morphological studies of sensory mutants indicate that many of the above capabilities derive from the amphidial sense organs (Lewis and Hodgkin, 1977; Albert et al., 1981; Hedgecock et al., 1985; Perkins et al., 1986). Response to light touch is localized to 6 neurons whose microtubule-fllled mechanocilia lie along the lateral margins of the head, body, and tail (Chalfie et al., 1985). No sensory mutant has yet shown morphological changes restricted to the phasmids, but several chemosensory and osmotic avoidance mutants show similar defects in both amphids and phasmids (Perkins et al., 1986).
The phasmids appear likely on anatomical grounds to be chemosensory. The changes in phasmidial staining or in phasmidial cilia ultrastructure noted in several chemosensory mutations support this conclusion (Perkins et al., 1986). Their extreme posterior placement suggests comparison of phasmid signals with signals to the anterior amphids. Because the phasmids could be involved in detecting both attractants and repellents, and because each contains 2 ciliated neurons (PHA, PHB), we speculate that the synapses of one neuron class might promote forward movement; the other, backward movement. Indeed, the synaptic output of PHA and PHB are strikingly different, as discussed below.
Bilaterally homologous sensory cells are probably functionally identical. There are 4 pairs of bilaterally homologous sensory cells (PLM, PHA, PHB, PHC), which are very nearly mirror images of one another at all anatomical levels from gross cell position down to their axon and dendritic projections. There remains the question whether 2 sensory homologues act in concert with one another or in a lateralized manner, perhaps for purposes of orientation. Lateralization seems unlikely for many reasons. The paired sensilla for PHA, PHB, and PHC are arranged so close to one another and in such an orientation as to effectively preclude differential stimulation of one member of the pair. Chalfie and Sulston (1981) have reported that laser ablation of a single member of the PLM pair "does not detectably affect touch sensitivity." Also, the 2 homologous members of a sensory pair often form gap junctions and/or chemical synapses onto one another. The gap junctions, in particular, are difficult to reconcile with the notion of lateralized function. Finally, the synaptic outputs from the homologous members of a sensory pair, rather than occurring to separate neurons for potentially separate parallel processing, are instead largely overlapping. This feature is not evident in Figure 9, where homologues are combined, but can be seen in Tables 3 and 4, where they are kept separate. As noted above, the excess of ipsilateral contacts by some sense cells seems to reflect incomplete mixing of left and right lumbar processes near the posterior limit of the preanal ganglion.
Sensory information from the tail is primarily converged onto a few major interneurons. The output of most tail receptors converges onto AVA, AVD, and PVC interneurons (Fig. 9). A model of the ventral-cord circuitry based upon laser ablations of motoneurons or interneurons (Chalfie et al., 1985; Chalfie and White, 1988) suggests that PVC and AVB interneurons can stimulate class B motoneurons to promote forward locomotion, while AVA and AVD interneurons can stimulate class A motoneurons to promote backwards locomotion. This model for forward versus backward motion is reasonably consistent with neurophysiological and biochemical studies of identified motoneurons in a larger nematode species, Ascaris (Stretton et al., 1985). We speculate that the very common PHB->AVA, PVC synapses may underlie an escape response. If the PHB cells were sensitive to chemical repellents, the net effect of PHB excitation of PVC would be to promote rapid forward movement and hence escape. The simultaneous PHB contacts onto AVA might be inhibitory, shutting down backwards motion, thus sharpening the escape response. Similarly, stimulation of the PHC mechanoreceptors could also excite PVC and result in forward movement. The gap junctions found in the posterior ventral nerve cord between the PLM touch neurons and PVC interneurons (Chalfie et al., 1985; White et al., 1986) are consistent with this general notion. These speculations may be testable by selective laser ablations or perhaps by genetic dissection of the circuits.
The PHA chemoreceptors are well situated to allow comparisons between amphid and phasmid. PHA sense cells synapse primarily onto other sense cells and onto the AVG interneuron. The sensory feedback of PHA onto other tail receptors might serve to inhibit other sensory modalities during PHA activity. From the wiring diagrams of White et al. (1986), the following circuit is evident:
The PHA outputs onto AVG can potentially conduct a phasmidial signal to the head, where AVG synapses via large gap junctions onto the RIF interneurons. In the nerve ring, RIF interneurons also receive processed sensory signals from amphidial chemoreceptors via the AIA interneurons. Thus, RIF interneurons may compare processed chemosensory signals from head and tail. In turn, the RIF interneurons have prominent synaptic inputs onto the AVB interneurons, which may reset the animals body motion in response to the compared chemical stimuli. As noted above, the AVB interneurons are prominent components of the ventral cord wiring, contacting class B motoneurons along the length of the body and thus controlling forward motion.
The dyadic synapse provides a basic unit for processing. One of the most striking features of the preanal ganglion circuitry is the preponderance of dyadic synapses. The 2 postsynaptic partners in a given contact are almost never homologous (Table 5); this makes sense if the function of the dyadic synapse is to diverge the information into distinct channels with different opportunities for modification. We presume that the 2 postsynaptic partners are affected simultaneously and proportionately by the presynaptic neuron. In many cases, the 2 postsynaptic cell types make direct contact with one another elsewhere, and most such contacts are in a single direction (Fig. 9). This circumstance can be represented diagrammatically as follows:
where A is the original presynaptic cell, and B and C are the 2
original postsynaptic partners. In this circumstance ("feed-forward"), cell C may receive 2 versions of an initial synaptic
output from cell A; the first is direct, via the original dyadic
synapse, and the second is indirect, and potentially modified,
through cell B. The indirect version, of course, could depend
on the state of cell B; it might arrive with a time delay, with
either an enhancing or an opposing effect, with an altered duration, and so forth. This basic 3-cell configuration could serve
a variety of functions, for example, prolongation of the signal's
effets, gating the signal's effects with respect to a threshold in
cell C or selecting for signals with a pronounced rate of change.
Dyadic and triadic synapses are well known anatomically in many other sensory ganglia, both in vertebrates and in invertebrates, but have not been widely studied physiologically. While their function is not yet well understood, current information seems compatible with the divergence/reconvergence idea presented above. Specific combinations of postsynaptic partners are also known to be preferred at tetradic photoreceptor terminals in the fly's visual system (Nichol and Meinertzhagen, 1982; Fröhlich, 1987), and feedback relationships of these synapses appear to be functionally plastic (Kral and Meinertzhagen, 1989). Dyads are involved in feedback relationships in the dragonfly ocellar retina (Klingman and Chappell, 1978) and in both feed-forward and feedback relationships in the visual system of the desert ant (Meyer, 1979). Physiological studies of vertebrate dyadic synapses have explored their feedback relationships (cf. Byzov and Golubtsov, 1978; Raviola and Dacheux, 1987). (In the vertebrate literature, dyadic synapses are often called "triads," and triadic synapses may be called "tetrads." In other instances, "triads" may refer to serial synapses.)
Infrequent synapse classes. There are many synapses listed in Table 3 that do not fall into one of the common synapse classes; that is to say, they involve a postsynaptic partner that is rarely contacted at all, or rarely by the particular presynaptic neuron. Because practically all of the individual synapse categories involve relatively low numbers on an absolute scale, it is difficult to define an infrequent synapse class on a simple numerical criterion. Depending upon what criterion is selected, infrequent synapses may represent 10-25% of all contacts.
Within the synaptically active cell group listed in Table 5, infrequent synapse classes accounted for only 28 of the 427 contacts observed in B126 and B136, suggesting that they played a minor role, at best, in the functions of that group. A majority of the infrequent synapse classes are due to the presynaptic involvements of only 4 cell types, PHA, PHC, PVN and DVB, which contact many less active cell types. PHA and PHC each form several frequent synapse classes, while DVB forms 1 and PVN forms no frequent synapse class. DVB and PVN also make synapses to hypodermal cells (see Table 3). Thus, the choice of postsynaptic partners by some neurons may be relatively non-specific and promiscuous, in contrast to the rules governing the formation of the frequent synapse classes. The PHA data in Table 3 demonstrate this tendency rather clearly, as their many postsynaptic targets do not fall into any highly repeated groups.
The behavioral role of the infrequent synapse classes is unclear. Walthall and Chalfie (1988) have suggested that certain classes of chemical synapse may have no behavioral function in C. elegans but are formed as a byproduct of an axonal guidance mechanism and, thereafter, retained to preserve the relative position of the presynaptic processes within a fiber bundle. However, in their example, the synapses from AVM-> BDU are actually rather frequent in the rostral portion of the ventral cord. Another possibility is that some neurons function in a way that requires only that they have a rather diffuse output, not a specific one. As an example, they might function in a relatively non-specific modulatory way, providing general neuronal activation or deactivation. Such neuromodulation might be effective at a distance from the presynaptic release sites, influencing many neurons which are not in direct contact (Barchas et al., 1978). This would allow infrequent synapse classes to be somewhat variable while still maintaining a rationale for their existence and for their concentration within a few presynaptic cell types.
Developmental noise The infrequent synapse classes formed by cells other than PVN, PHA, PHC, or DVB are quite widely distributed among a number of pre- and postsynaptic participants. Almost all of them are nonreproducible, and they usually contain 1, sometimes 2, contacts per class. It seems unlikely that they are of behavioral importance; instead, they seem to us to represent developmental "noise" of some sort. One possibility is that they represent the residue of synapse classes that were more frequent at an earlier developmental stage. One instance of developmental rewiring, involving the loss of some synapses and the gain of others, has been reported for C. elegans (White et al., 1978). Another possibility is that infrequent synapse classes represent a secondary consequence of whatever mechanisms operate to establish the frequent synapse classes. This would be an example of developmental noise as described by Waddington (1957). Macagno et al. (1973) noted a similar background scatter of infrequent connections in the Daphnia optic lamina, where each receptor cell forms frequent synapses (20-80 contacts) onto a particular lamina cell and a lesser or equal number of contacts onto unidentified processes. Besides these frequent synapses, much smaller numbers of synapses go to other lamina cells or even to other receptor cell processes. Some of these infrequent synapses also appear to be obeying patterns, but some others, perhaps a few percent of the total, are sufficiently unusual to indicate that they represent developmental noise. The well-studied development of the optic lamina makes it unlikely that this noise represents the residue of previously frequent synapse classes.
The existence of developmental noise of the Waddington type seems reasonable in evolutionary terms. If selection during evolution is simply for appropriate function, and if this function is carried out principally by the frequent synapse classes, then there seems to be little reason why programs evolved to establish the frequent classes should undergo further refinement, probably at additional informational cost, simply to eliminate a minority of behaviorally unimportant synapses.
Combinatorial specification of synapse development. A reproducible pattern among the frequent synapse classes has been noted in the preanal ganglion in 3 animals (Tables 4, 5). It is intriguing to note that (1) these synapses are almost all dyadic, (2) bilateral homologues are rarely contacted simultaneously, (3) several different dyadic combinations occur at different frequencies, and (4) many possible combinations of synaptic partners never occur. The combinatorial aspects of this pattern are particularly striking, suggestive of the requirement for simultaneous recognition of different postsynaptic recognition factors from 2 separate partners before a synapse can be formed. Mutant alleles that fail to form many chemical synapses are already known to be viable in C. elegans (Hall et al., 1989). Mutations of synaptic recognition factors are likely to produce viable alleles as well, probably having an uncoordinated phenotype. Currently, more than 100 unc genes have been isolated as viable mutant alleles and mapped on the genome (see Wood, 1988). Thus, the preanal ganglion presents a model system in which to explore the genetics of synapse specification.
Web adaptation, Thomas Boulin, for Wormatlas, 2002