Suppression of foreign synapses

281 Nature Vol. 260 March 25 1976 news and views WHEN a foreign nerve is implanted into a normally .i nnervated skeletal muscle, it grows out over .the surface of the muscle fibres but does not synapse with •them. If, at this juncture, the normal innervation is r·emoved by cutting or crushing the nerve, then the foreign nerve will now form functional synapses on the denervated fibres. The original nerve eventually regenerates and synapses again with the muscle. This resu1ts in muscle fibres which have been 'tricked' into accepting innervation from two sources. The subsequen,t fate of these dually innervwted fibres as currently of great interest •to neurobiologists, since one can ask the basic question of whether .the fmeign innervation is recognised, and somehow suppressed or removed in favour of the orJginal. Such a mechanism could be of considerable impor.t•ance in trying to accoum for the great specificity and plastic·ity of connections that is exhibited by the nervous system. The principal proponents of such a mechanism have been Mark and his colleagues who have provided evidence that in both goldfish eye muscle (Marotte and Mark, Brain Res., 19, 41, 53; 1970) and adult salamander muscle (Cass et a/., Nature , 243, 201; 1973), .t he foreign innervation can be functionally suppressed. Fur.thermore, they have claimed •that the suppressed synapses are not retracted, but remain on the muscle fibre and appear normal when ex·a mined in ·t he electron microscope (Manotte and Mark, Brain Res. , 1.9, 53; 1970). The assay for function in the goldfish eye muscle was indirect, involving behavioural11:esting of the eye movements, and their interpretation of ·the results is currently controversial since a repetition and extension of these experiments has led to the conclusion that the foreign innervation is not suppressed (Scot•t, Science, 189, 644; 1975). Meanwhile, in several other sJtuations, including one where the d·ifferent synapses were formed on a neurone, the du·al innervation has proved perfectly stable with no evidence of suppression, even after several months (Frank et al., Nature, 247, 375; 1974 and Purves, Nature, 256, 589; 1975). But in a timely contribution (;this .issue of Nature, page 350), Yip and Dennis have provided clear dectrophysiologioal evidence that suppression does .take place in dually innervated fibres of the· adult newt. By intracellular recording from individual Suppression of foreign synapses from Jeremy Brockes muscle fibres, they .h ave been able to show t hat transmitter release from the foreign nerve .terminals is reduced as a consequence of re-innervation by the original nerve. Specifically, •t he amplitude of .the synaptic potential decreases during the first two months following re--innervation. The synaptic potential is derived from a number of packe•ts, or quanta, of transmitter that are recruited synchronously by stimulating the nerve. By analysing a number of fibres at different 11:imes during the period of suppress-ion, Yip and Dennis hav,e shown that .t he number of packets recru·ited (the 'quanta] content') declines while the amount of transmitter in a single packet does not change significantly. This is a most important insight into the suppression process, since it characterises ~t as a presynaptic effect on .t ransmitter release rather than a postsynaptic eff·e ct on, for example, the chemosensitivity of the muscle membrane. An ·i mportant que·stion, which has yet .to be answered, concerns t·h e eventual fate of .the suppressed synapses. Are foreign synapses withdrawn from .the muscle when the original nerve re•turns, or do they remain structurally intact but functionally suppressed, as suggested by Mark and his colleagu,es? When, after six months, the original nerve was inl1:errupted for a second time, Yip and Dennis found •that .the re-establishment of functional transmission .t hrough the foreign nerve appeared to occur more rapidly than after the ·initial operation. This suggests .t hat •the foreign nerve axons remain in relatively intimate contact with the musdc, but does not necessari.ly mean thM foreign synapses are present. In ·an analogous si,t uation during normal development, it is known that mammalian skeletal muscle fibres are muJ,tiply innervated before birth {Redfern, J. Physiol., Lond., 209, 701; 1970; Bennett and Pettigrew, J. Physiol., Lond. , 241, 515; 9174); when this muUiple innervation is © 1976 Nature Publishing Group eliminated during development, the extra synapses are completed retracted. ALthough this process <is not identical to .t hat observed by Yip •a nd Dennis, it does illustrate that competitive ·interactions between synapses can lead to the removal of ex.t ra innervation. Meanwhile, one wonders wha•t rules govern the operation of suppr·ession, and why irt did not take place in several other situations. Is it, •as Yip and Dennis suggest, a question of retaining in the aduH newt a faculty which is normally confined to development, or js i1t perhaps related to the way that foreign and original synapses are distributed along .t he length of the muscle fibres? J.t would be interesting to determine whether the foreign nerve in Yip and Dennis's study can become the correct one when •t he reciprocal experiment is performed in its own muscle. The most helpful insights, however, will probably come from an analysis of the mechanism. One would like .to know if the interaction has to occur between synapses that are relatively close (of the order of microns) or whether it can occur over distances of the order of millimetres. If the laJtter is so, one might suspect that the muscle fibre plays a direct role in the process. An informative experiment could be to .take a muscle that is only partially re~innerva,ted by the orginal nerve, and determine if the suppressive influence can aot on foreign synapses pr·esent on adjacent fibres .t hat were not re-i'nnervated. A second major question, which I have considered above, concerns the effect of the interaction on the ana,tomy of the suppressed synapses. If we knew the answers to these two questions, then the number of plausible mechanisms would ·be reduced. I do not think Jtha.t we can distinguish these possibili·ties with the available evidence, but some should be clearly excluded by an anatomical study. Other questions, such as the role of activitty in the two nerves, and in the muscle fibre , also seem approachable. This whole probl·em illustrates the advantage of working on the neuromuscular junction~a preparation with which one can ask a bask question about synaptic function , and hope to answer .j.t at several levels. Fuf\thermore , thel'e is every reason to believe that these answers will prove relevant to rthe experimentally less accessible situation of synapses in the central nervous sys.tem.  (...truncated)