Signal transduction
and regulation of
neurotrophins Donald Ludwig Our
for Cancer Research, London,
Institute
understanding
has been greatly
of the
molecular
enhanced
several new neurotrophic
of neurotrophic
by neuronal
Opinion
activity
in activity-dependent
development
The past few years have seen tremendous progress in the study of neurotrophic factors and their receptors. The nerve growth factor (NGF) family, collectively termed the neurotrophins, has been expanded to include at least four additional members, brain-derived neurotrophic factor (BDNF) [l], neurotrophin-3 (NT-3) 12-71, NT-4 [8], and most recently, NT-5 [9]. In addition, the crystal structure of NGF has finally been solved [lo*], a general structure that is probably shared among the neurotrophins because of their high degree of homology. Finally, a component of the long-elusive ‘high-affinity’ receptor for NGF has been discovered to be encoded by the trk proto-oncogene [ll*-13-l and receptors for other neurotrophins encoded by other members of the trk! family [9,14*-17*].
interactions
Neurotrophic
of
factors
in the central nervous processes throughout
and maturity.
in Neurobiology
Introduction
UK
isolation and characterization
factors and their receptors.
and may be involved
Current
nature
by the recent
have been found to be regulated system,
C. Lo
1992, 2:33f+340
neurotrophic regulation of development and maintenance of the nervous system that is much more complex than had previously been suspected. Not surprisingly, evidence is accumulating which suggests that abnormalities in neurotrophic factor production and/or responsiveness are involved in neurological disorders such as Alzheimer’s and Parkinson’s diseases [ 22,231, and epilepsy (see [24-l >. But even as these complex longer-term actions of the neurotrophic factors are becoming increasingly apparent, many shorter-term phenomena involving neurotrophic factors are emerging that may be equally important. In particular, this review will discuss progress in the past year or so in two ares-among a wealth of other research-that implicate neurotrophic factors in biological events on a time scale shorter than that into which they have been more traditionally put: the molecular nature of the initial signal-transduction events triggered by neurotrophins, and the regulation of neurotrophin production by neuronal activity.
Much progress has also been made in our understanding of the biological actions of neurotrophic factors, and of the neurotrophins in particular. NGF remains the prototypical neurotrophic factor-its roles in the promotion of neuronal survival and differentiation, and in the maintenance of neuronal phenotype, are the most well characterized (for a review, see [18]). Additional functions of NGF and the other neurotrophins are, however, fast emerging, particularly in the central nervous system. Neurotrophins have been found to promote the survival of a number of central neuronal populations in culture; for example, NGF and BDNJ! support the survival and differentiation of cultured central choline@ neurons [ 191, and BDNF supports the dopaminergic neurons of the substantia nigra [20,21]. Similarly, the degeneration of the cholinergic neurons of the basal forebrain following transection of their projections to the hippocampus and cortex is significantly reduced by administration of NGF (for a review, see [ 181).
NGF binding to neurons is comprised of ‘high-a&&y’ (Qw 10-11) and ‘low-affinity’ (IQ” 10-9) components; the biological effects of NGF are associated primarily with high-affinity binding, which constitutes about 10% of total binding sites on NGF-responsive cells (see [25]>. Signal transduction of the other neurotrophins may operate similarly. The first neurotrophin receptor to be isolated was a low-affinity receptor for NGF that by itself was not sufficient to mediate the biological effects of NGF (for a review, see [ 251). Although commonly referred to as the low&nity NGF receptor, it has since been shown to bind BDNF, NT3, and NT-4 with similar afkities [5,8,14*,26].
These and other findings suggest wide-ranging roles for the neurotrophins, each factor having multiple and changing actions during development, and a system of
Recently, the trk proto-oncogene was found to encode a receptor for NGF [ llg-13-l and, subsequently, trkL3 was found to encode a receptor for BDNF, NT-3, NT-4 and
The receptors
for neurotrophins
Abbreviations BDNF-brain-derived NC&nerve
336
growth
neurotrophic factor;
factor;
EGF-pidermal
NMDA-N-methyl-o-aspartate;
@
Current
Biology
growth
factor;
ERK---extracellular
NT-3-neurotrophin-3;
Ltd ISSN 0959-4388
signal-regulated
PLC-y,-phospholipase
kinase; C-y,.
Signal transduction and regulation of neurotrophins
NT-5, but not NGF [8,9,14*-16*], and trkCa receptor for NT-3 [17-l. Interestingly, NT-5 has also been found to activate trk [9], reinforcing the notion of a combinatorial relationship among homologous neurotrophins and their receptors. The trk encoded receptors are membrane receptor tyrosine kinases, confkming previous studies that linked protein tyrosine kinase activity with the high-affinity receptor complex [ 271. The trk receptors closely resemble archetypal growth factor receptors, such as those for epidermal growth factor (EGF) and fibroblast growth factors [ 281; all three contain within their cytoplasmic regions a catalytic domain that bears closest homology to the insulin receptor subfamily of protein tyrosine kinases [17*,29,30]. The trk receptors are required for high-afkity neurotrophin binding [31*,32], and have come to be referred to loosely as the ‘highafhnity’ receptors for neurotrophins. High-a&&y NGF binding appears, however, to derive from a complex containing both the trk receptor and the low-aflinity receptor [ 31.1. Expression of either receptor alone in COS cells results in only low-aflkrity binding, but their co-expression leads to high a&&y binding. Similarly, fibroblasts expressing trkB alone exhibit only low-affinity binding for BDNF and NT-3 [ 15.1. Proper signal transduction of NGF, which is associated with high-affinity binding, also appears to be dependent on both trk and low-affinity receptors. In particular, a functional low-affinity receptor seems to be critical for the functioning of the high-a&r&y receptor complex. Mutations in the cytoplasmic domain of the low-affinity receptor, which has no tyrosine kinase activity of its own, can block high-affinity binding and tyrosine phosphoty lation of cellular proteins [33]. Additionally, PC-12 cells expressing chimeric EGF/low-affinity NGF receptors undergo neuron-like differentiation in response to EGF, al though the trk receptor is presumably unaltered in these experiments [34]. Other experiments, however, have suggested that highalhnity NGF binding can arise from the expression of the trk receptor alone [35]. The majority of receptors so expressed bind NGF with low-affinity, as in cells that express both receptors [12*]. Similarly, NT-3 appears to bind with both high and low afkity to trkC [ 17.1. Furthermore, an antibody that blocks NGF binding to the low-affinity receptor blocks low-affinity binding, but does not alfect one class of highatfmity binding or the biological effects of NGF on PC 12 cells [ 361. Indeed, trk receptors are able to mediate many biological processes in the absence of the low-affinity receptor, emphasizing that the neurotrophin receptors may play different roles depending on the biological contexts in which they are expressed. For example, meiotic maturation can be induced by NGF in Xenopus oocytes expressing only the trk receptor, but not in those expressing only the low-al&-&y receptor [37]. NGF has been shown to be a mitogen (in conjunction with basic fibroblast growth factor) for cultured neuroepithelial stem cells [38], and NT3 a mitogen for cultured neural crest progenitor cells [ 391. NIH 3T3 fibroblasts expressing trk, but not the low-affinity neurotrophin receptor,
Lo
proliferate in response to NGF and, interestingly, NT-3 [40*]. Similarly, BDNF and NT-3 are mitogenic for 3T3 cells expressing trkB [ lti,41*], and NT-3 is mitogenic for those expressing trkC [ 17.1. The identification of the trk family as receptor tyrosine kinases suggests that there may be important rapid cellular responses to neurotrophins in addition to their longer term actions. Receptor tyrosine kinases are, in general, rapidly activated by ligand binding, and the trk receptors are no exception. The autophosphorylation of trk induced by NGF [ 11.1, and trkB by BDNF or NT-3 [15-l, is well under way within a minute. The activation of the NGF receptor leads rapidly to the phosphorylation of other proteins, including a number of immediate early genes (for a review, see [42]). While much of this activation of cellular machinery presumably leads to patterns of gene expression that underlie neuronal survival and differentiation, there may be immediate actions that affect neuronal behavior in the short term (for a review, see [43]). For example, NGF rapidly stimulates a number of cellular signalling proteins, including phospholipase C-y1 (PLC-)I~) [4446]. Several extracellular signal-regulated kinases (EFKs), including MAP2 kinase, are activated by tyrosine phosphotylation within minutes of exposure to NGF [47,48] ; whether MAP2 kinase and other ERKs are activated directly by trk receptors remains in question [ 491. The ERKs are serine/threonine protein kinases, and, along with PLC-)I~, are among a cascade of intracellular signalling molecules triggered by neurotrophins that may alter ongoing neuronal function. Regulation
of neurotrophins
by neuronal
ktivity In many regions of the central nervous system, the neurotrophins, in turn, appear to be highly regulated by neuronal activity. This seems to be true in particular for the hippocampus, where the highest levels of neurotrophin expression seem to occur (see [ 501). In the hippocampus, levels of mRNAs encoding NGF and BDNF increase by some tenfold within a few hours after experimentally-induced seizures, and with a latency of a few hours increase in other regions including the neocortex [ 24*,51,52*,53*]. The increases for BDNF mRNA are particularly dramatic: a peak of over sixfold in BDNF mRNA levels is reached in the dentate gyrus within 30 min after electrical stimulation of seizure activity in rats [24-l. Lesion-induced seizures result in even higher levels of BDNF mRNA, although with a slower time course; levels in the dentate gyrus CA1 region peak 6 h post-lesion at nearly 40 times control levels [53*]. In both experimental systems, even a single epileptiform afterdischarge is sufficient to increase levels of NGF and BDNF mRNA significantly (Fig.1) [53-l. These increases in mRNAs are transient; their levels largely return to pre-seizure levels after 24 h [ 24*,53*]. Seizure activity appears to increase neurotrophin mRNA levels only in those areas that already express these factors at least at low levels [53-l, BDNF is distnbuted more broadly than NGF in the central nervous system, and so its up-regulation by electrical activity is similarly
337
338
Signalling
mechanisms
of a suspected ‘positive feedback mechanism implicated in the progression of epilepsy. In the kindling model of epileptogenesis, long-term synaptic changes are thought to result from recurrent stimuli and lead to maintained hyperexcitability and increased susceptibility to seizure. In fact, the intraventricular administration of antiserum against NGF has been shown to delay the development of amygdaloid kindling [ 591. New roles for neurotrophic
Fig.1. Increased expression
of brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus after a single epileptiform afterdischarge, shown by in situ hybridization. (A) Control. (B) Two hours after the onset of seizure activity. sp, CA3 stratum pyramidale. sg, stratum granulosum. Photograph courtesy of CM Call and JC Lauterborn, reproduced with permission from L53.1.
more widespread [24*,53*]. BDNF is, however, regu lated differently and, in general, more rapidly than NGF in several areas, particularly in the neocortex [53*]. In contrast, NT-3 mRNA levels do not appear to be affected by seizure activity [ 24.1, or decrease below pre-seizure levels by 12 h Cj Iauterborn, personal communication). Similar increases of NGF and BDNF can be induced by injections of glutamate receptor agonists, or by their administration to hippocampal neurons in culture [52-l. Kainate, a glutamate receptor agonist, can induce BDNF levels in cultured hippocampal neurons by over tenfold within 3 h; these and similar increases in NGF mRNAs seem to be mediated specifically by non-N-methylD-aspartate (NMDA)-type receptors [52-l. Injections of kainate can also produce increases in NGF and BDNF mRNAs in vivq these increases are similarly blocked by antagonists of non-NMDA glutamate receptors, such as NBQX [24*,52-l. Significantly, increases in both NGF and BDNF mRNAs can also be induced in culture by depolarization with high K+, consistent with the idea that electrical activity of neurons is the common element in these experiments that leads to increased production of neurotrophins. These large and rapid increases in neurotrophin production may, in turn, mediate the synaptic reorganization and hyperexcitability in me hippocampus that is observed after limbic seizures [54-581. If so, it would be tempting to speculate that the neurotrophins form part
factors?
The rapid and considerable regulation of neurotrophin production by neuronal activity implicates neurotrophins generally in activity-dependent processes in the central nervous system. Under normal conditions, such processes may involve neurotrophins in some forms of synaptic plasticity, but under abnormal conditions, the same or similar processes may contribute to the progression of such neurological disorders as epilepsy. The activity-dependent regulation of neurotrophins potentially puts the full range of neurotrophic actions under the control of neuronal activity, and may implicate neurotrophins in long-term activity-dependent processes such as learning and memoty. That many of these experiments have been performed in adult animals suggests that roles for neurotrophins in the nervous system, far from ending after the initial stages of growth and development, persist in maturity and may change in their nature. The identification of the t& family of gene products as receptors for the neurotrophins reveals that receptor ty rosine kinases mediate the initial signal transduction of neurotropl$s, and suggests many short-term actions of neurotrophins in addition to their better-characterized long-term actions. Furthermore, the recasting of neurotrophins as mitogens in some cases where the t& receptors are expressed in the absence of the lowaffinity receptor adds to the already blurred distinction between growth and differentiation factors, Such experi ments emphasize that binding specificity between ligand and receptor is but one aspect of the recognition and interpretation of neurotrophic signals (see [6O]). These and other advances in our understanding of the biology of neurotrophic factors are greatly expanding our view of their roles in the development, maintenance and routine functioning of the nervous system. Further investigations and discoveries of novel factors will no doubt continue to do so, and reveal a multitude of ‘new’ roles for neurotrophic factors. Acknowledgements I would like to thank MV Chao and JC Iauterborn for their helpful comment5 during the preparation of the manuscript.
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KIM U-H, FINK D JR, KIM HS, PARKDJ, CONTRERAS ML, GUROFF G, RHEE SG: Nerve Growth Factor Stimulates Phosphorylation of Phospholipase C-y in PC12 Cells. J Biol Cbem 1991, 266:1359-1362.
47.
BOULTONTG, NYE SH, ROBBINS DJ, IP NY, RADZIEJEW~KA E, MORGENBESSER SD, DEPINHO RA, PANAYOTATOS N, COBB
D-Aspartate Receptor Plasticity in Kindling: Quantitative and Qualitative Alterations in the N-Methyl-D-Aspartate Receptor-Channel Complex. Proc Nat1 Acud Sci USA 1989,
is the Speci-
DC Lo, Ludwig Institute for Cancer Research, 91 Riding House Street, London WZP SBT, UK, and Department of Neurobiology, Duke University Medical Center, Box 3209, Durham, North Carolina 27710, USA
and regulation of
neurotrophins Donald Ludwig Our
for Cancer Research, London,
Institute
understanding
has been greatly
of the
molecular
enhanced
several new neurotrophic
of neurotrophic
by neuronal
Opinion
activity
in activity-dependent
development
The past few years have seen tremendous progress in the study of neurotrophic factors and their receptors. The nerve growth factor (NGF) family, collectively termed the neurotrophins, has been expanded to include at least four additional members, brain-derived neurotrophic factor (BDNF) [l], neurotrophin-3 (NT-3) 12-71, NT-4 [8], and most recently, NT-5 [9]. In addition, the crystal structure of NGF has finally been solved [lo*], a general structure that is probably shared among the neurotrophins because of their high degree of homology. Finally, a component of the long-elusive ‘high-affinity’ receptor for NGF has been discovered to be encoded by the trk proto-oncogene [ll*-13-l and receptors for other neurotrophins encoded by other members of the trk! family [9,14*-17*].
interactions
Neurotrophic
of
factors
in the central nervous processes throughout
and maturity.
in Neurobiology
Introduction
UK
isolation and characterization
factors and their receptors.
and may be involved
Current
nature
by the recent
have been found to be regulated system,
C. Lo
1992, 2:33f+340
neurotrophic regulation of development and maintenance of the nervous system that is much more complex than had previously been suspected. Not surprisingly, evidence is accumulating which suggests that abnormalities in neurotrophic factor production and/or responsiveness are involved in neurological disorders such as Alzheimer’s and Parkinson’s diseases [ 22,231, and epilepsy (see [24-l >. But even as these complex longer-term actions of the neurotrophic factors are becoming increasingly apparent, many shorter-term phenomena involving neurotrophic factors are emerging that may be equally important. In particular, this review will discuss progress in the past year or so in two ares-among a wealth of other research-that implicate neurotrophic factors in biological events on a time scale shorter than that into which they have been more traditionally put: the molecular nature of the initial signal-transduction events triggered by neurotrophins, and the regulation of neurotrophin production by neuronal activity.
Much progress has also been made in our understanding of the biological actions of neurotrophic factors, and of the neurotrophins in particular. NGF remains the prototypical neurotrophic factor-its roles in the promotion of neuronal survival and differentiation, and in the maintenance of neuronal phenotype, are the most well characterized (for a review, see [18]). Additional functions of NGF and the other neurotrophins are, however, fast emerging, particularly in the central nervous system. Neurotrophins have been found to promote the survival of a number of central neuronal populations in culture; for example, NGF and BDNJ! support the survival and differentiation of cultured central choline@ neurons [ 191, and BDNF supports the dopaminergic neurons of the substantia nigra [20,21]. Similarly, the degeneration of the cholinergic neurons of the basal forebrain following transection of their projections to the hippocampus and cortex is significantly reduced by administration of NGF (for a review, see [ 181).
NGF binding to neurons is comprised of ‘high-a&&y’ (Qw 10-11) and ‘low-affinity’ (IQ” 10-9) components; the biological effects of NGF are associated primarily with high-affinity binding, which constitutes about 10% of total binding sites on NGF-responsive cells (see [25]>. Signal transduction of the other neurotrophins may operate similarly. The first neurotrophin receptor to be isolated was a low-affinity receptor for NGF that by itself was not sufficient to mediate the biological effects of NGF (for a review, see [ 251). Although commonly referred to as the low&nity NGF receptor, it has since been shown to bind BDNF, NT3, and NT-4 with similar afkities [5,8,14*,26].
These and other findings suggest wide-ranging roles for the neurotrophins, each factor having multiple and changing actions during development, and a system of
Recently, the trk proto-oncogene was found to encode a receptor for NGF [ llg-13-l and, subsequently, trkL3 was found to encode a receptor for BDNF, NT-3, NT-4 and
The receptors
for neurotrophins
Abbreviations BDNF-brain-derived NC&nerve
336
growth
neurotrophic factor;
factor;
EGF-pidermal
NMDA-N-methyl-o-aspartate;
@
Current
Biology
growth
factor;
ERK---extracellular
NT-3-neurotrophin-3;
Ltd ISSN 0959-4388
signal-regulated
PLC-y,-phospholipase
kinase; C-y,.
Signal transduction and regulation of neurotrophins
NT-5, but not NGF [8,9,14*-16*], and trkCa receptor for NT-3 [17-l. Interestingly, NT-5 has also been found to activate trk [9], reinforcing the notion of a combinatorial relationship among homologous neurotrophins and their receptors. The trk encoded receptors are membrane receptor tyrosine kinases, confkming previous studies that linked protein tyrosine kinase activity with the high-affinity receptor complex [ 271. The trk receptors closely resemble archetypal growth factor receptors, such as those for epidermal growth factor (EGF) and fibroblast growth factors [ 281; all three contain within their cytoplasmic regions a catalytic domain that bears closest homology to the insulin receptor subfamily of protein tyrosine kinases [17*,29,30]. The trk receptors are required for high-afkity neurotrophin binding [31*,32], and have come to be referred to loosely as the ‘highafhnity’ receptors for neurotrophins. High-a&&y NGF binding appears, however, to derive from a complex containing both the trk receptor and the low-aflinity receptor [ 31.1. Expression of either receptor alone in COS cells results in only low-aflkrity binding, but their co-expression leads to high a&&y binding. Similarly, fibroblasts expressing trkB alone exhibit only low-affinity binding for BDNF and NT-3 [ 15.1. Proper signal transduction of NGF, which is associated with high-affinity binding, also appears to be dependent on both trk and low-affinity receptors. In particular, a functional low-affinity receptor seems to be critical for the functioning of the high-a&r&y receptor complex. Mutations in the cytoplasmic domain of the low-affinity receptor, which has no tyrosine kinase activity of its own, can block high-affinity binding and tyrosine phosphoty lation of cellular proteins [33]. Additionally, PC-12 cells expressing chimeric EGF/low-affinity NGF receptors undergo neuron-like differentiation in response to EGF, al though the trk receptor is presumably unaltered in these experiments [34]. Other experiments, however, have suggested that highalhnity NGF binding can arise from the expression of the trk receptor alone [35]. The majority of receptors so expressed bind NGF with low-affinity, as in cells that express both receptors [12*]. Similarly, NT-3 appears to bind with both high and low afkity to trkC [ 17.1. Furthermore, an antibody that blocks NGF binding to the low-affinity receptor blocks low-affinity binding, but does not alfect one class of highatfmity binding or the biological effects of NGF on PC 12 cells [ 361. Indeed, trk receptors are able to mediate many biological processes in the absence of the low-affinity receptor, emphasizing that the neurotrophin receptors may play different roles depending on the biological contexts in which they are expressed. For example, meiotic maturation can be induced by NGF in Xenopus oocytes expressing only the trk receptor, but not in those expressing only the low-al&-&y receptor [37]. NGF has been shown to be a mitogen (in conjunction with basic fibroblast growth factor) for cultured neuroepithelial stem cells [38], and NT3 a mitogen for cultured neural crest progenitor cells [ 391. NIH 3T3 fibroblasts expressing trk, but not the low-affinity neurotrophin receptor,
Lo
proliferate in response to NGF and, interestingly, NT-3 [40*]. Similarly, BDNF and NT-3 are mitogenic for 3T3 cells expressing trkB [ lti,41*], and NT-3 is mitogenic for those expressing trkC [ 17.1. The identification of the trk family as receptor tyrosine kinases suggests that there may be important rapid cellular responses to neurotrophins in addition to their longer term actions. Receptor tyrosine kinases are, in general, rapidly activated by ligand binding, and the trk receptors are no exception. The autophosphorylation of trk induced by NGF [ 11.1, and trkB by BDNF or NT-3 [15-l, is well under way within a minute. The activation of the NGF receptor leads rapidly to the phosphorylation of other proteins, including a number of immediate early genes (for a review, see [42]). While much of this activation of cellular machinery presumably leads to patterns of gene expression that underlie neuronal survival and differentiation, there may be immediate actions that affect neuronal behavior in the short term (for a review, see [43]). For example, NGF rapidly stimulates a number of cellular signalling proteins, including phospholipase C-y1 (PLC-)I~) [4446]. Several extracellular signal-regulated kinases (EFKs), including MAP2 kinase, are activated by tyrosine phosphotylation within minutes of exposure to NGF [47,48] ; whether MAP2 kinase and other ERKs are activated directly by trk receptors remains in question [ 491. The ERKs are serine/threonine protein kinases, and, along with PLC-)I~, are among a cascade of intracellular signalling molecules triggered by neurotrophins that may alter ongoing neuronal function. Regulation
of neurotrophins
by neuronal
ktivity In many regions of the central nervous system, the neurotrophins, in turn, appear to be highly regulated by neuronal activity. This seems to be true in particular for the hippocampus, where the highest levels of neurotrophin expression seem to occur (see [ 501). In the hippocampus, levels of mRNAs encoding NGF and BDNF increase by some tenfold within a few hours after experimentally-induced seizures, and with a latency of a few hours increase in other regions including the neocortex [ 24*,51,52*,53*]. The increases for BDNF mRNA are particularly dramatic: a peak of over sixfold in BDNF mRNA levels is reached in the dentate gyrus within 30 min after electrical stimulation of seizure activity in rats [24-l. Lesion-induced seizures result in even higher levels of BDNF mRNA, although with a slower time course; levels in the dentate gyrus CA1 region peak 6 h post-lesion at nearly 40 times control levels [53*]. In both experimental systems, even a single epileptiform afterdischarge is sufficient to increase levels of NGF and BDNF mRNA significantly (Fig.1) [53-l. These increases in mRNAs are transient; their levels largely return to pre-seizure levels after 24 h [ 24*,53*]. Seizure activity appears to increase neurotrophin mRNA levels only in those areas that already express these factors at least at low levels [53-l, BDNF is distnbuted more broadly than NGF in the central nervous system, and so its up-regulation by electrical activity is similarly
337
338
Signalling
mechanisms
of a suspected ‘positive feedback mechanism implicated in the progression of epilepsy. In the kindling model of epileptogenesis, long-term synaptic changes are thought to result from recurrent stimuli and lead to maintained hyperexcitability and increased susceptibility to seizure. In fact, the intraventricular administration of antiserum against NGF has been shown to delay the development of amygdaloid kindling [ 591. New roles for neurotrophic
Fig.1. Increased expression
of brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus after a single epileptiform afterdischarge, shown by in situ hybridization. (A) Control. (B) Two hours after the onset of seizure activity. sp, CA3 stratum pyramidale. sg, stratum granulosum. Photograph courtesy of CM Call and JC Lauterborn, reproduced with permission from L53.1.
more widespread [24*,53*]. BDNF is, however, regu lated differently and, in general, more rapidly than NGF in several areas, particularly in the neocortex [53*]. In contrast, NT-3 mRNA levels do not appear to be affected by seizure activity [ 24.1, or decrease below pre-seizure levels by 12 h Cj Iauterborn, personal communication). Similar increases of NGF and BDNF can be induced by injections of glutamate receptor agonists, or by their administration to hippocampal neurons in culture [52-l. Kainate, a glutamate receptor agonist, can induce BDNF levels in cultured hippocampal neurons by over tenfold within 3 h; these and similar increases in NGF mRNAs seem to be mediated specifically by non-N-methylD-aspartate (NMDA)-type receptors [52-l. Injections of kainate can also produce increases in NGF and BDNF mRNAs in vivq these increases are similarly blocked by antagonists of non-NMDA glutamate receptors, such as NBQX [24*,52-l. Significantly, increases in both NGF and BDNF mRNAs can also be induced in culture by depolarization with high K+, consistent with the idea that electrical activity of neurons is the common element in these experiments that leads to increased production of neurotrophins. These large and rapid increases in neurotrophin production may, in turn, mediate the synaptic reorganization and hyperexcitability in me hippocampus that is observed after limbic seizures [54-581. If so, it would be tempting to speculate that the neurotrophins form part
factors?
The rapid and considerable regulation of neurotrophin production by neuronal activity implicates neurotrophins generally in activity-dependent processes in the central nervous system. Under normal conditions, such processes may involve neurotrophins in some forms of synaptic plasticity, but under abnormal conditions, the same or similar processes may contribute to the progression of such neurological disorders as epilepsy. The activity-dependent regulation of neurotrophins potentially puts the full range of neurotrophic actions under the control of neuronal activity, and may implicate neurotrophins in long-term activity-dependent processes such as learning and memoty. That many of these experiments have been performed in adult animals suggests that roles for neurotrophins in the nervous system, far from ending after the initial stages of growth and development, persist in maturity and may change in their nature. The identification of the t& family of gene products as receptors for the neurotrophins reveals that receptor ty rosine kinases mediate the initial signal transduction of neurotropl$s, and suggests many short-term actions of neurotrophins in addition to their better-characterized long-term actions. Furthermore, the recasting of neurotrophins as mitogens in some cases where the t& receptors are expressed in the absence of the lowaffinity receptor adds to the already blurred distinction between growth and differentiation factors, Such experi ments emphasize that binding specificity between ligand and receptor is but one aspect of the recognition and interpretation of neurotrophic signals (see [6O]). These and other advances in our understanding of the biology of neurotrophic factors are greatly expanding our view of their roles in the development, maintenance and routine functioning of the nervous system. Further investigations and discoveries of novel factors will no doubt continue to do so, and reveal a multitude of ‘new’ roles for neurotrophic factors. Acknowledgements I would like to thank MV Chao and JC Iauterborn for their helpful comment5 during the preparation of the manuscript.
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DC Lo, Ludwig Institute for Cancer Research, 91 Riding House Street, London WZP SBT, UK, and Department of Neurobiology, Duke University Medical Center, Box 3209, Durham, North Carolina 27710, USA
