Los Angeles

Date:
1981
Reference:
PP/CRI/E/1/29/18
Catalogue details

Licence: In copyright

Credit: Los Angeles. Source: Wellcome Collection.

    26/41
    one transmitter. In what follows we review briefly the origin of Dale's Principle and the recent evidence for multiple-transmitter status. THE AUTHENTIC DALE'S PRINCIPLE: CHEMICAL UNITY The idea first called Dale's Principle by Eccles et al. mitter, but that the same chemical transmitter is re leased from all the synaptic terminals of a neurone. In this statement, transmitter is used in the singular, but the emphasis is on the chemical unity of a neuron, and chemical unity is the essence of the idea originally de veloped by Dale (1935a,b). The two versions of Dale's Principle are not necessarily consistent. It might be argued that a neuron found to secrete two or more transmitters at all of its synaptic terminals is a particu larly strong exemplar of the authentic version. Indeed, Eccles in his retrospective account of the origin of the term Dale's Principle (Eccles, 1976, p. 227) says, I proposed that 'Dale's Principle' be defined as stating that at all the axonal branches of a neurone there was stances [emphasis added]. Our main concern in this paper is the idea that a neuron secretes only one trans mitter, and particularly Dale's view of this idea, but we begin with the origin of the authentic version because almost all statements of it, including the first (Eccles et al., 1954), refer to transmitter in the singular. Dale's interest in the apparent chemical unity of a neuron arose in 1934 in connection with the possibility of chemical transmission in the mammalian central nerv ous system. In two public lectures (Dale 1935a,b), Dale reviewed evidence for chemical transmission in the peripheral nervous system and then turned his attention to a possible way to investigate central transmission. His line of thought was as follows: (1) Langley and Anderson's cross-union experiments on the peripheral nervous system, at the turn of the century, are all con sistent with the idea that cholinergic axons can replace each other, and adrenergic axons can replace each other, but axons of different chemical function are not exchangeable. (2) Because in these experiments a regen erated axon apparently displayed the original chemical function of the parent cell body, regardless of the transmitter preference of the new target cells, chemical function is evidently the same throughout a whole neu ron and not alterable. (3) Thus it is possible that a sen sory neuron that releases a transmitter peripherally dur ing antidromic vasodilatation releases the same transmitter centrally, and identification of the transmit ter in the periphery would provide a plausible candidate for the central transmitter. Dale's cautious statement of this idea in his much-quoted Dixon Memorial Lecture (1935b) was as follows: with vasodilatation and the other at a central synapse, can we suppose that the discovery and identification of a chemical transmitter of axon-reflex vasodilatation would at a central synapse? The possibility has at least some value as a stimulus to further experiment. In all his other statements of this idea known to us, Dale was similarly cautious (a letter to Feldberg of Sep tember 4, 1934, reproduced in Paton, 1976; Dale 1935a; 1937; 1938b,c; 1952, reproduced in Dale, 1954). Ob viously the idea did not strike him as a matter of Eccles' interest in the idea of chemical unity within a creted by cat motor neurons at collateral endings on Renshaw cells. In 1954, Eccles et al. produced evidence that the transmitter at the collateral endings is ACh, as at the endings in skeletal muscle. In their text they refer to Dale's postulate of chemical unity and an expec tation that ACh would prove to be the transmitter of the collateral endings; in their summary, the observed chemical unity becomes Dale's Principle. It may be noted that this case, upon which Dale's suggestion was elevated to the status of principle, is not yet complete because the transmitter secreted by motor neurons onto each other at collateral synapses (e.g., Cullheim et al., 1977) has not been investigated. Dale derived the idea of chemical unity from the experimental observation that a regenerated axon appears to have the same transmitter status as the parent cell body. Eccles found a more general justification for it in his Bancroft Memorial Lecture (1957a; see also 1957b): Now there is a principle enunciated by Dale (1935) which operates by the same kind of transmitter substance at all of its branches. It will readily be appreciated that the same mechanical manufacturing goes on throughout the whole extent of a cell, and that a cell cannot make one kind of transmitter substance for some of its terminals and another kind for others of its terminals. [The refer ence to Dale is given here as 1935b.] What Is the Current Standing of the Authentic Dale's Principle? A variety of neurons in vertebrates and invertebrates (e.g., Kandel and Gardner, 1972) have been shown to release the same transmitter at more than one site, but no case is known to us in which all the major branches of a neuron or synapses on different types of target cells have been examined. That is to say, we know of no case that could serve as a foundation for a genuine principle. Nor do we know of a convincing counter-example. Present knowledge of the polarized fine structure of many types of neurons suggests the need for the same caution in assuming chemical unity at synapses as was displayed by Dale in his lectures of 1934. In vertebrates, dendrites characteristically differ in fine structure from axons; perhaps in certain neurons the dendrites, or a distinctive subset of dendrites, will be found to display a different unity with respect to transmitter choice from that displayed by the axon and its terminals. Indeed, Shepard (1979) raises the possibility that the mitral cells of the mammalian olfactory bulb release a different transmitter from their dendrites than from their axons. It is of interest that the chemical unity in secretion en visaged by Dale and by Eccles (1957a,b) has no current standing in other branches of cell biology. For example, introductory textbooks suppose that a mammalian liver cell secretes bile from its surfaces that face bile canaliculi and serum proteins from its surfaces that face capillar ies. In this case, polarized fine structure is comfortably associated with secretion of different substances at dif ferent points on the cell surface. Moreover, cases are now known in which a neuron controls certain target cells via chemical synapses and other target cells via electrical synapses (e.g., the Aplysia neuron called LIO and vertebrate photoreceptors); in some of these cases the synapses made by a single axon are not uniform in chemistry. Finally, in the case of neurons that display histochemical reactivity for more than one active sub stance and that make synapses at diverse sites or of di verse form, is it safe to assume that the same transmit ter or combination of transmitters is released at all the synapses? The possibility that different materials are transported in the peripheral and central branches of vertebrate primary sensory neurons is discussed by Ochs et al. (1978). In our view, the current standing of Dale's idea is ex actly that expressed by Dale in 1934: identification of a transmitter secreted by one branch of a neuron provides a useful hint about the synaptic mechanisms else- While the origin of the authentic Dale's Principle can be traced clearly through Eccles et al. (1954) and Eccles (1976) to an idea expressed by Dale (1935a,b), the origin of the single-transmitter version is less clear to us. In the current discussions of multiple-transmitter status, the origin of this popular version has been given as Dale (1935b), if it has been given at all; however, while transmitter is used in the singular throughout that lecture, no statement in that lecture has the intent of the popular version. The first clear expression known to us of the popular version (although it was not called Dale's Principle) occurs in Eccles et al. (1956), a paper that reported the presence of an inhibitory interneuron in the la inhibitory pathway to spinal motor neurons. Eccles et al. stated: was supposed that there was no interneurone on the di rect inhibitory pathway, it had to be postulated that a group la afferent fibre manufactured and liberated both [given here as Brock et al., 1952]. V a relaying synapse in this pathway, making contact with motoneurons ic fibres n of the exclusive release of a single trans mitter substance from any given nerve cell, such as has system (cf. 12,19) [given here as Dale, 1935b; and Feld- berg, 1954] . . . .The insertion of an intermediate neu- garded as a device for changing the chemical transmitter operating on the next cell in the pathway, the ability to In this passage and in other writings (e.g., Eccles, 1957b, 1962, 1969), it is clear that Eccles liked the sim plicity and potential usefulness of the idea that neurons are exclusively excitatory or inhibitory, and therefore, by inference, secrete only one transmitter. The devel opment of Eccles' thinking on this subject, and the in applicability in Aplysia of the idea that a neuron is either excitatory or inhibitory, have been reviewed by Kandel (1968, 1976) and Kandel and Gardner (1972). That the same idea is not universally applicable in ver tebrates is suggested, for example, by evidence that in bullfrog sympathetic ganglia, the preganglionic axons are directly responsible not only for the fast excitatory postsynaptic potentials, but also for the slow inhibitory postsynaptic potentials in principal neurons (Horn and Dodd, 1981). In the passage quoted above, Eccles et al. (1956) as sociated Dale with the exclusive release of a single popular version of Dale's Principle. Is this association valid? Dale clearly preferred the idea that each periph- does not secrete both ACh and NE is implicit in his terms cholinergic and adrenergic. However, in the context of the atropine-resistant effects of the vagus on the gut and of certain parasympathetic neurons on blood vessels, he repeatedly considered the possibility that these neurons collectively secrete more than one transmitter (e.g., Dale, 1929; Dale and Gaddum, 1930; Dale, 1933a, 1934, 1935a, 1938a.c; a letter to Feldberg of August 22, 1962, reproduced in Paton, 1976). In these writings, Dale does not explicitly raise the possi bility of co-secretion of ACh and a second transmitter by individual neurons, but because he thought of para sympathetic neurons as cholinergic, he may have consid ered this possibility. Dale's discussion of atropine-resistant vagal and para sympathetic effects, and his rationalization of the idea that only the one transmitter, ACh, is involved, are of contemporary interest, not only because there is mount