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Plasticity of autonomic transmission
137
Plasticity of autonomic transmission G. Burnstock Department of Anatomy and Developmental Biology, University College London. Gower Street, London WCIE 6BT, U.K.
In the past few years, there has been a major change in our understanding of autonomic control mechanisms [2]. The autonomic neuromuscular junction consists of extensive terminal nerve fibres which contain varicosities from which transmitter is released 'en passage' to reach smooth muscle cells that are in electrical communication with each other via gap-junctions. The varicosities do not have a fixed relationship with particular smooth muscle cells and the minimum distance between varicosities and muscle cells ranges from about 20 nm in densely innervated tissues such as vas deferens and iris to as much as 2 ~ m in large elastic arteries. Muscle cells do not have postjunctional specialisations. Thus, the autonomic neuromuscular junction differs from synapses, such as the skeletal neuromuscular junction, where there is an established relationship with both pre- and postsynaptic specialisations. In addition to noradrenaline (NA) and acetylcholine (ACh), other neurotransmitters are present in autonomic nerves, including adenosine 5'-triphosphate (ATP), 5-hydroxytryptamine (5-HT), dopamine, and a number of peptides, notably neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), enkephalin, somatostatin, cholecystokinin, substance P (SP), and calcitonin generelated peptide (CGRP). There is now compelling evidence that some, if not all, nerve cells store and release more than one transmitter [1,3]. Systematic studies reveal specific combinations of transmitter substances ('chemical coding') for different neurone types which project to particular effector tissues and have defined central connections. The predominant 'codings' are: sympathetic nerves, NA, ATP and NPY;
parasympathetic nerves, ACh and VIP; sensorymotor nerves, SP, C G R P and ATP; and intrinsic neurones in gut, heart, bladder and airways, some with combinations of up to 6 putative transmitters. A neuromodulator is defined as a substance that modifies the process of neurotransmission. It may act as a prejunctional modulator by decreasing or increasing the amount of neurotransmitter released by a nerve varicosity, or it may act as a postjunctional modulator by altering the time course or extent of action of a transmitter. There are many reports of both pre- and postjunctional modulation occurring at the autonomic neuromuscular junction. Endothelial receptors that mediate vasodilatation via the release of endothelium-derived relaxing factor include receptors for ATP, SP and 5-HT, as well as ACh. Recent immunocytochemical studies have localised choline acetyltransferase (the synthetic enzyme for ACh), 5-HT, angiotensin II, vasopressin and SP within vascular endothelial cells. These substances are released during increased flow (shear stress) or hypoxia. It is suggested that, while both perivascular nerves and endothelial systems interplay in the normal physiological control of vascular tone, during pathophysiological circumstances such as ischaemia there is a more dominant role for endotheliummediated responses as a protective mechanism against tissue hypoxia. Autonomic neuroeffector systems show a high degree of plasticity, even in mature adult animals. Changes in expression of transmitters and cotransmitters in autonomic nerves occur during development and aging, after chronic exposure to drugs, in a number of disease situations, and in
138
the nerves that remain following trauma or surgery [4]. Studies of the mechanisms involved in the control of co-transmitter and receptor expression are now needed. Superimposed on the genetic programming of transmitter and receptor expression during development and aging, several different types of 'trophic', adaptive mechanisms may be operating, including those involving growth factors, levels of activity in nerves, local regulators of gene expression and circulating hormones. It is suggested that compensatory increases in innervation or transmitter expression should be considered by pathologists as well as loss or damage of nerves; and further, since the expression of cotransmitters and receptors varies so
markedly with age, sex and pathological history. this should be taken into account ira designing therapeutic treatments.
References 1 Burnstock, G., Do some nerve cells release more than one transmitter?, Neuroscience, 1 (1976) 239-248. 2 Burnstock, G., The changing face of autonomic neurotransmission. (The First von Euler Lecture in Physiology.), Acta Physiol. Scand., 126 (1986)67-91. 3 Burnstock, G., Cotransmission. The Fifth Heymans Lecture, Gent, 1990., Arch. Int. Pharmacodyn. Ther. 304(1990) 7-33. 4 Burnstock, G., Changes in expression of autonomic nerves in aging and disease, J. Auton. Nerv. Syst., 30 (1990) 525-534.
Structural and functional modifications of ganglionic in the frog
alter axotmny
D. Eugrne and J. Taxi D~partement de Cytologic, lnstitut des Neurosciences, C.N.R.S., Universitd Pierre et Marie Curie. 7 Quai Saint-Bernard, Paris. Franc~
In the amphibia, the few works devoted to the effects of axotomy on ganglionic transmission have led to contradictory results [1,2]. We have therefore reinvestigated these effects in the frog Rana esculenta.
Axotomy was carried out on the two last ganglia of the lumbar sympathetic chain by sectioning all the rami communicantes with the sciatic plexus. The effects were analyzed from 3 days to 4 months following axon section. Synaptic transmission was studied by means of intracellular microelectrodes in response to orthodromic stimulation of the preganglionic nerve fibres. After each electrophysiological experiment, the ganglia were prepared for electron microscopy. The number of synapses was counted directly on the screen of the electron microscope. In normal ganglia, 10 Hz suprathreshold preganglionic stimulation triggered postsynaptic action potentials in all the neurones, whereas after axotomy, the same stimulation could trigger subthreshold excitatory post-synaptic potentials
(EPSPs) in some neurones. The first effects on synaptic transmission were detected at 4 days. At one week, 29% of neurones showed subthreshold EPSPs. At 2 weeks and one month, both the number of neurones showing EPSPs and the occurrence of these EPSPs increased. Moreover, at one month, the EPSP amplitude was smaller than that at one week. indicating a strong depression in synaptic transmission. At 2 and 4 months, the number of neurones showing EPSPs and the occurrence of EPSPs decreased. But at 4 months. there were still about 25% of neurones showing subthreshold EPSPs. In electron microscopy, the synapses were identified by their synaptic complexes. A "synaptic index' was defined as the ratio of the number of encountered synapses to the number of explored perikarya. An index of 'simple contacts' was also calculated on a similar basis. A simple contact corresponded to a synapse-like contact without synaptic complexs. At 4 days after axotomy, the synaptic index had begun to decrease. At one
Plasticity of autonomic transmission G. Burnstock Department of Anatomy and Developmental Biology, University College London. Gower Street, London WCIE 6BT, U.K.
In the past few years, there has been a major change in our understanding of autonomic control mechanisms [2]. The autonomic neuromuscular junction consists of extensive terminal nerve fibres which contain varicosities from which transmitter is released 'en passage' to reach smooth muscle cells that are in electrical communication with each other via gap-junctions. The varicosities do not have a fixed relationship with particular smooth muscle cells and the minimum distance between varicosities and muscle cells ranges from about 20 nm in densely innervated tissues such as vas deferens and iris to as much as 2 ~ m in large elastic arteries. Muscle cells do not have postjunctional specialisations. Thus, the autonomic neuromuscular junction differs from synapses, such as the skeletal neuromuscular junction, where there is an established relationship with both pre- and postsynaptic specialisations. In addition to noradrenaline (NA) and acetylcholine (ACh), other neurotransmitters are present in autonomic nerves, including adenosine 5'-triphosphate (ATP), 5-hydroxytryptamine (5-HT), dopamine, and a number of peptides, notably neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), enkephalin, somatostatin, cholecystokinin, substance P (SP), and calcitonin generelated peptide (CGRP). There is now compelling evidence that some, if not all, nerve cells store and release more than one transmitter [1,3]. Systematic studies reveal specific combinations of transmitter substances ('chemical coding') for different neurone types which project to particular effector tissues and have defined central connections. The predominant 'codings' are: sympathetic nerves, NA, ATP and NPY;
parasympathetic nerves, ACh and VIP; sensorymotor nerves, SP, C G R P and ATP; and intrinsic neurones in gut, heart, bladder and airways, some with combinations of up to 6 putative transmitters. A neuromodulator is defined as a substance that modifies the process of neurotransmission. It may act as a prejunctional modulator by decreasing or increasing the amount of neurotransmitter released by a nerve varicosity, or it may act as a postjunctional modulator by altering the time course or extent of action of a transmitter. There are many reports of both pre- and postjunctional modulation occurring at the autonomic neuromuscular junction. Endothelial receptors that mediate vasodilatation via the release of endothelium-derived relaxing factor include receptors for ATP, SP and 5-HT, as well as ACh. Recent immunocytochemical studies have localised choline acetyltransferase (the synthetic enzyme for ACh), 5-HT, angiotensin II, vasopressin and SP within vascular endothelial cells. These substances are released during increased flow (shear stress) or hypoxia. It is suggested that, while both perivascular nerves and endothelial systems interplay in the normal physiological control of vascular tone, during pathophysiological circumstances such as ischaemia there is a more dominant role for endotheliummediated responses as a protective mechanism against tissue hypoxia. Autonomic neuroeffector systems show a high degree of plasticity, even in mature adult animals. Changes in expression of transmitters and cotransmitters in autonomic nerves occur during development and aging, after chronic exposure to drugs, in a number of disease situations, and in
138
the nerves that remain following trauma or surgery [4]. Studies of the mechanisms involved in the control of co-transmitter and receptor expression are now needed. Superimposed on the genetic programming of transmitter and receptor expression during development and aging, several different types of 'trophic', adaptive mechanisms may be operating, including those involving growth factors, levels of activity in nerves, local regulators of gene expression and circulating hormones. It is suggested that compensatory increases in innervation or transmitter expression should be considered by pathologists as well as loss or damage of nerves; and further, since the expression of cotransmitters and receptors varies so
markedly with age, sex and pathological history. this should be taken into account ira designing therapeutic treatments.
References 1 Burnstock, G., Do some nerve cells release more than one transmitter?, Neuroscience, 1 (1976) 239-248. 2 Burnstock, G., The changing face of autonomic neurotransmission. (The First von Euler Lecture in Physiology.), Acta Physiol. Scand., 126 (1986)67-91. 3 Burnstock, G., Cotransmission. The Fifth Heymans Lecture, Gent, 1990., Arch. Int. Pharmacodyn. Ther. 304(1990) 7-33. 4 Burnstock, G., Changes in expression of autonomic nerves in aging and disease, J. Auton. Nerv. Syst., 30 (1990) 525-534.
Structural and functional modifications of ganglionic in the frog
alter axotmny
D. Eugrne and J. Taxi D~partement de Cytologic, lnstitut des Neurosciences, C.N.R.S., Universitd Pierre et Marie Curie. 7 Quai Saint-Bernard, Paris. Franc~
In the amphibia, the few works devoted to the effects of axotomy on ganglionic transmission have led to contradictory results [1,2]. We have therefore reinvestigated these effects in the frog Rana esculenta.
Axotomy was carried out on the two last ganglia of the lumbar sympathetic chain by sectioning all the rami communicantes with the sciatic plexus. The effects were analyzed from 3 days to 4 months following axon section. Synaptic transmission was studied by means of intracellular microelectrodes in response to orthodromic stimulation of the preganglionic nerve fibres. After each electrophysiological experiment, the ganglia were prepared for electron microscopy. The number of synapses was counted directly on the screen of the electron microscope. In normal ganglia, 10 Hz suprathreshold preganglionic stimulation triggered postsynaptic action potentials in all the neurones, whereas after axotomy, the same stimulation could trigger subthreshold excitatory post-synaptic potentials
(EPSPs) in some neurones. The first effects on synaptic transmission were detected at 4 days. At one week, 29% of neurones showed subthreshold EPSPs. At 2 weeks and one month, both the number of neurones showing EPSPs and the occurrence of these EPSPs increased. Moreover, at one month, the EPSP amplitude was smaller than that at one week. indicating a strong depression in synaptic transmission. At 2 and 4 months, the number of neurones showing EPSPs and the occurrence of EPSPs decreased. But at 4 months. there were still about 25% of neurones showing subthreshold EPSPs. In electron microscopy, the synapses were identified by their synaptic complexes. A "synaptic index' was defined as the ratio of the number of encountered synapses to the number of explored perikarya. An index of 'simple contacts' was also calculated on a similar basis. A simple contact corresponded to a synapse-like contact without synaptic complexs. At 4 days after axotomy, the synaptic index had begun to decrease. At one