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Introduction: Retrograde messengers
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THE NEUROSCIENCES,V o l 5, 1993 : p 147
Introduction: Retrograde messengers John Garthwaite THIS ISSUE IS entitled 'retrograde messengers', in deference to the hypothesis that there is a factor that is generated postsynaptically but which passes to presynaptic nerve terminals to influence neurotransmitter release and thereby bring about enduring changes in synaptic strength. The best studied example of such synaptic plasticity is 'long-term potentiation', or LTP, in the hippocampus (although many other brain areas exhibit a similar phenomenon). A key event in the initiation of L T P is an influx of Ca 2§ into postsynaptic elements through the N M D A (N-methyl-D-aspartate) type of glutamate receptor; at least one phase of L T P itself is believed to reflect a subsequent enhancement of presynaptic glutamate release. Consequently, a good candidate for the retrograde messenger would be one that is generated in a Ca2+-dependent manner on N M D A receptor activation, is freely diffusible across membranes, and is able, under appropriate circumstances, to increase vesicular glutamate release. Currently, two candidates--arachidonic acid and nitric oxide--are under especially close scrutiny, and these molecules form the focus of the present issue. Despite the title, the putative functions of these messengers are not restricted to that of a retrograde, trans-synaptic, messenger. In principle, both could diffuse widely from a given source to influence a variety of structures within a three-dimensional space
whose volume may be equivalent to that of thousands of synapses. This, in itself, brings a new dimension to inter-cellular signalling within the central nervous system as it breaks with the comfortable notion that communication occurs at spatially restricted loci (synapses), between neurons, and in one direction. These messengers could communicate between neuronal, glial, vascular and other elements, without the sources and targets being in close anatomical juxtaposition. Many important questions arise, not least of which is how a specificity of action is incorporated into this type of signalling system. With these considerations in mind, this issue has been arranged so that some of the articles concentrate specifically on the mechanisms of hippocampal LTP, with particular regard to the identity of the retrograde messenger (J.H. Williams et al, K.A. Clark et al, E.M. Schuman and D.V. Madison). Nitric oxide has also been implicated in other forms of synaptic plasticity, and K. Shibuki highlights the possible importance of nitric oxide in long-term depression of synaptic transmission in the cerebellum. Other articles (D. Attwell et al, J. Garthwaite) deal more generally with arachidonic acid and nitric oxide as neural messengers andJ. Bockaert et al and B. Mayer concentrate on the biochemical and receptor mechanisms linked to the generation of these molecules, and the pathways of signal transduction.
We[[come Research Laboratories, Langley Court, South Eden Park Road, Beckenham, Kent BR3 3BS, UK @1993 Academic Press Ltd 147
THE NEUROSCIENCES,V o l 5, 1993 : p 147
Introduction: Retrograde messengers John Garthwaite THIS ISSUE IS entitled 'retrograde messengers', in deference to the hypothesis that there is a factor that is generated postsynaptically but which passes to presynaptic nerve terminals to influence neurotransmitter release and thereby bring about enduring changes in synaptic strength. The best studied example of such synaptic plasticity is 'long-term potentiation', or LTP, in the hippocampus (although many other brain areas exhibit a similar phenomenon). A key event in the initiation of L T P is an influx of Ca 2§ into postsynaptic elements through the N M D A (N-methyl-D-aspartate) type of glutamate receptor; at least one phase of L T P itself is believed to reflect a subsequent enhancement of presynaptic glutamate release. Consequently, a good candidate for the retrograde messenger would be one that is generated in a Ca2+-dependent manner on N M D A receptor activation, is freely diffusible across membranes, and is able, under appropriate circumstances, to increase vesicular glutamate release. Currently, two candidates--arachidonic acid and nitric oxide--are under especially close scrutiny, and these molecules form the focus of the present issue. Despite the title, the putative functions of these messengers are not restricted to that of a retrograde, trans-synaptic, messenger. In principle, both could diffuse widely from a given source to influence a variety of structures within a three-dimensional space
whose volume may be equivalent to that of thousands of synapses. This, in itself, brings a new dimension to inter-cellular signalling within the central nervous system as it breaks with the comfortable notion that communication occurs at spatially restricted loci (synapses), between neurons, and in one direction. These messengers could communicate between neuronal, glial, vascular and other elements, without the sources and targets being in close anatomical juxtaposition. Many important questions arise, not least of which is how a specificity of action is incorporated into this type of signalling system. With these considerations in mind, this issue has been arranged so that some of the articles concentrate specifically on the mechanisms of hippocampal LTP, with particular regard to the identity of the retrograde messenger (J.H. Williams et al, K.A. Clark et al, E.M. Schuman and D.V. Madison). Nitric oxide has also been implicated in other forms of synaptic plasticity, and K. Shibuki highlights the possible importance of nitric oxide in long-term depression of synaptic transmission in the cerebellum. Other articles (D. Attwell et al, J. Garthwaite) deal more generally with arachidonic acid and nitric oxide as neural messengers andJ. Bockaert et al and B. Mayer concentrate on the biochemical and receptor mechanisms linked to the generation of these molecules, and the pathways of signal transduction.
We[[come Research Laboratories, Langley Court, South Eden Park Road, Beckenham, Kent BR3 3BS, UK @1993 Academic Press Ltd 147