- Email: [email protected]
Do adrenergic chromaffin cells exocytose like noradrenergic cells
LETTERS TO THE EDITOR Trinucleotide-repeat expansions and neurodegenerative diseases Albin and Tagle ~ presented an excellent review, in TINS, of the current molecular studies of Huntington's disease (HD). The discoveries of more diseases that are caused by unstable trinucleotide-repeat expansions raise numerous important questions. The similarities between the neurodegenerative diseases HD, dentatorubral-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type I (SCAI) and Machado-Joseph disease (MJD) are of particular interest. All of these diseases are autosomal dominant, have variable penetrance, involve genetic anticipation, and have been linked to an expansion of the CAG repeat, which encodes a polyglutamine tract, in the coding regions of unrelated, widely expressed genes. This results in similar neurodegeneration, possibly via an excitotoxic mechanism, of specific subsets of neurons in HD (Ref. 2) and in DRPLA (Ref. 3). A neurodegenerative mechanism is suggested whereby the translation or degradation, or both, of the huntingtin protein, containing an expanded polyglutamine tract, would cause subtle, chronic alterations in uptake of glutamine or release of glutamine, or both. Consequently, this would have an impact on cellular and
vascular concentrations of glutamate to an extent proportional to the length of the polyglutamine tract. The subtle alterations in glutamate levels might affect neurons chronically that are sensitive specifically to the concentration of glutamate, via glutamate receptors. The relationship of polyglutamine-tract expansion, and onset of neurodegeneration, could thus be mediated by a concentration effect on chronic sensitization or desensitization of this subset of affected neurons. There are a number of lines of experimental evidence that support such a crucial role for glutamate in the neurodegenerative diseases HD, DRPLA, SCAI and MJD. (I) Glutamate can act as a neurotoxin when released into the extracellular space under hypoxic-ischemic conditions4, even at relatively low concentrationss. (2) Hypoxic neuronal injury in cortical cultures can be attenuated by removal of glutamine, a glutamate precursor, from the culture medium6. (3) Quinolinate, a glutamate analogue that binds the NMDA receptor preferentially, has been found to cause selective cell death in the striatum 7 in a pattern identical to that found in HD patients.
Do adrenergic chromaffin cells exocytose like noradrenergic cells? Three recent reviews in TINS ~-3 attest to the current interest in neuroendocrine secretion. One review pointed out specific differences in secretory processes between pituitary lactrotrophs and adrenal chromaffin cells3 while another implied differences in pancreatic cells~; none questioned whether adrenergic and noradrenergic chromaffin cells, which together constitute the experimental model that is most often chosen for these studies, have the same exocytotic mechanism. Many data, however, document significant differences in the secretory nature of adrenergic and noradrenergic cells4-7. Does the well-known selective liberation of adrenaline and noradrenaline from the adrenal gland in situs result from differential innerration or is it a result of differential modulation of the secretory process in its two principal chromaffin-cell populations? A recent report 9 might shed light on this 440
TrNSVol. 18, No. 10, 1995
question: it showed that the growthassociated protein GAP-43, when introduced experimentally into permeabilized cultured bovine chromaffin cells, acts as a brake to exocytosis by activating a granulebound G protein. Whether GAP-43 is involved in neuroendocrine secretion depends on whether it is present in vivo. Since our initial observation on the expression of GAP-43 in noradrenergic chromaffin cells in the adult adrenal gland ~°, other laboratories tl-13 have also been unable to detect it in adrenergic chromaffin cells. Negative data cannot of course exclude low levels of protein expression but if GAP-43 is active in chromaffin cells, it is more likely to be so in noradrenergic rather than in adrenergic cells. The role of GAP-43 in chromaffin cells, suggested by Vitale and colleagues9, can thus operate only in noradrenergic cells, that is, -20% of chromaffin cells in
(4) Levels of the NMDA receptor are decreased in the striatum of HD patients8, indicating that surviving neurons have few or no NMDA receptors. This evidence, correlated with the recent genetic data that link the neurodegenerative diseases HD, DRPLA, SCAI and MJD, suggests that experimental investigation of a common excitotoxic cellular mechanism of neurodegeneration might increase our understanding of these diseases. It might also point to potential therapies, including alteration of levels of glutamine and glutamate and the use of glutamate-receptor antagonists.
Anthony J. Hannan Developmental Neurobiology Unit, Children's Medical Research Institute, Locked Bag 23, Wentworthville, NSW 2145, Australia. References 1 Albin, R.L. and Tagle, D.A. (1995) Trends Neurosci. 18, 11-14 2 Huntington's Disease Collaborative Research Group (1993) Cell 72, 971-983 3 Koide, R. e t al. (1994) Nat. Genet. 6, 9-13 4 0 l n e y , J.W. and Sharpe, L.G. (1969) Science 166, 386-388 5 Choi, D.W. e t al. (1987) J. Neurosci. 7, 357-368 6 Goldberg, M.P. e t aL (1988) Neurosci. Left. 94, 52-57 7 Beal, M.F. e t al. (1986) Nature 321, 168-171 8 Young, A.B. e t al. (1988) Science 241, 981-983
bovine and rat glands. Adrenergic cells presumably secrete by a different mechanism or use a different protein that fulfils this function. GAP-43 is not the only 'typically' neuronal protein that is downregulated during the noradrenergic-adrenergic transition of chromoblasts. The cell adhesion molecule LI, which is probably involved in segregating noradrenergic from adrenergic cells during adrenal-gland histogenesis, is also undetectable in adrenergic cells t4. Reasons for such differences, and the differential expression of other proteins ~s'~6are, for the moment, obscure but might be related to the low levels of expression of glucocorticoid receptors in noradrenergic cells ~7. A search for genetic differences between the two principal phenotypes of catecholamine-containing chromaffin cells might provide explanations for these differences in both protein expression and secretory mechanisms. References 1 Blondel, O., Bell, G.I. and Seino, S. (1995) Trends Neurosci. 18, 157-161 2 Burgoyne, R.D. and Morgan, A. (1995) Trends Neurosci. 18, 191-196 3 Liedo, J-M. e t aL (1994) Trends Neurosci. 17, 426-432 4 Marley, P.D. and Livett, B.G. (1987)
LETTERS TO THE EDITOR Neurosci. Lett. 77, 81-86 5 Teraoka, H., Sugawara, T. a n d Nakazato, Y. (1993) I. Neurochem. 60, 1936-1940 6 Cahill, A.L. and Perlman, R.L. (1992) J. Neurochem. 58, 768-771 7 Choi, A.Y., Fukui, H. and Perlman, R.L. (1995) J. Neurochem. 64, 206-212 8 Feuerstein, G. a n d G u t m a n , Y. (1971) Br. I. Pharmacol. 43, 764-775 9 Vitale, N. e t al. (1994) J. Biol. Chem.
269, 30293-30298
10 Grant, N.J. et al. (1992) Eur. J. Neurosci. 4, 1257-1263 11 Lopez Costa, J.J. e t al. (1994) Cell Tissue Res. 275, 555-556 12 Holgert, H. et al. (1994) Dev. Brain Res. 83, 35-52 13 Dorsey, D.A. and Schmidt, R.E. (1993) Neurosci. Lett. 162, 29-33 14 Leon, C. et al. (1992) Eur. J. Neurosci. 4, 201-209
15 Happola, O. et al. (1985) Brain Res. 339, 393-396 16 Schultzberg, M. et al. (1989) Neuroscience 30, 805-810 17 Ceccatelli, S. e t al. (1989) Acta Physiol. Scand. 137, 559-560
Keith Langley and Nancy J. Grant INSERM, Unit6 338, 5 rue Blaise-Pascal, F-67084 Strasbourg cedex, France.
Do muscle-spindle afferents act as interneurons during mastication?
Rostral ,,,, ,,,,
II-_-~im - - I
Recently, Wall ~ discussed the active control of propagation through sensory afferents. In addition to primary-afferent depolarization (PAD) of synaptic regions, Wall presented evidence for a new form of GABA-mediated presynaptic control that blocks propagation at some distance from the terminals. We propose that these two mechanisms might be used to convert part of the axonal trees of trigeminal musclespindle afferents into premotor interneurons during mastication. When PAD is strong, it generates antidromic action potentials that propagate into peripheral nerves. It has long been assumed that the function of such antidromic firing is to decrease sensory inputs by colliding with orthodromic spikes2. However, when muscle-spindle afferents fire antidromically, motoneurons are excited 2, presumably because spikes that propagate toward the periphery from depolarized terminals also travel orthodromically down the branches to motoneurons. Bursts of antidromic potentials in sensory axons occur during several rhythmical motor patterns in paralysed animals (fictive movements), suggesting that sensory terminals are depolarized phasically by central pattern generators 3-6 (CPG). Axons of masseter muscle-spindle afferents, recorded caudal to the Vth motor nucleus during fictive mastication show bursts of what appear to be antidromic spikes in phase with activity in masseter motoneurons (jaw closure) (Fig.). During the opposite phase of the cycle, orthodromic spikes from the muscle fail to reach this part of the axon 7. The pattern of antidromic bursts7, and the subgroup of CPG interneurons that are active, change together with the pattern of fictive mastication8, suggesting that PAD might be switched between sets of terminals. In the rostral parts of the neuron, spikes pass during jaw closure, but at the same low frequency as the orthodromic traffic, suggesting that the antidromic bursts are blocked in jaw closure, while orthodromic spikes fail in the opposite phase9. Thus, transmission into different
regions of the axonal tree seems to be under the selective active control that Wall postulated, perhaps through axo-axonic synapses in a crucial region (shaded box). Coupled with PAD at terminals on subpopulations of neurons in the CPG, this might enable the caudal segment of the primary afferent to act as a lastorder interneuron during mastication, while the disconnected rostral segment transmits the peripheral input mono- and bisynaptically to provide phasic servoassistance during jaw closure.
III III IIIIIIIIIIIII
~
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~
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Motoneurons
A. Kolta J.P. Lund Facult~ de m6decine dentaire, Universit6 de Montr6al, C.P. 6128, succ. Centre-ville, Montr6al, Qu6bec, Canada H3C 3J7.
Myotatic-reflex interneurons
1
" ,,, IIII ,,,, IIII ,,r III ,,, ',',11 I1[I
........... t uron ~!~ups
K-G. Westberg Dept Physiology, University of Ume& S-901 87 Ume&, Sweden. P. Clavelou H6pital Fontmaure and Dept of Neurology, Centre H6pital et Universit6 de Clermont-ferraud, Chamali6res 63400, France. References 1 Wall, P.D. (1995) Trends Neurosci. 18, 99-103 2 Eccles, J.C., Kozac, W. and Magni, F. (1961) J. Physiol• 159, 128-146 3 Baev, K.V. (1978) Neurophysiology 10, 316-317 4 Dubuc, R. e t aL (1985) Brain Res. 359,
375-378 5 Richter, D.W. e t al. (1986) Pfl#gers Arch• 406, 12-19 6 Gossard, J-P. e t aL (1989) J. Neurophysiol. 62, 1177-1189
Caudal Fig. Diagram of a masseter spindle afferent and its connections. These neurons have cell bodies in the Vth mesencephalic nucleus, and a long descending axon that gives off branches at many levels1°. The incoming action potentials that are caused by tonic muscle stretch are shown (1), together with the patterns of firing that are recorded near the soma (2), and the subnucleus oralis (3) during fictive mastication. Note that the bursts in 3 occur in jaw closure, in phase with the motoneurons (4). We suggest that neurons of the central pattern generator (CPG) control the caudal terminals and transmission through the area that is indicated by the shaded box. 7 Clavelou, P. e t al. (1994) Soc. Neurosci. Abstr. 20, 1758 8 Westberg, K-G. e t al. (1994) Soc. Neurosci. Abstr. 20, 1758 9 Kolta, A. e t al. (1990) J. NeurophysioL 64, 1067-1076 10 Shigenaga, Y. e t al. (1988) Brain Res. 445, 392-399
Corrigendum In the article by R. Suzanne Zukin and Michael V.L. Bennett in the July issue of TINS (Vol. 18, pp. 306-313), the referencing of the Table in Box I was incorrect. References a, b, c, d, e and f, identifying the sources of alternative nomenclatures of NRI-receptor splice variants, should be b, c, cl, e, f and g, respectively. We apologise to the authors and to the readers for this error.
TINS VoI. 18, No. 10, 1995
441
vascular concentrations of glutamate to an extent proportional to the length of the polyglutamine tract. The subtle alterations in glutamate levels might affect neurons chronically that are sensitive specifically to the concentration of glutamate, via glutamate receptors. The relationship of polyglutamine-tract expansion, and onset of neurodegeneration, could thus be mediated by a concentration effect on chronic sensitization or desensitization of this subset of affected neurons. There are a number of lines of experimental evidence that support such a crucial role for glutamate in the neurodegenerative diseases HD, DRPLA, SCAI and MJD. (I) Glutamate can act as a neurotoxin when released into the extracellular space under hypoxic-ischemic conditions4, even at relatively low concentrationss. (2) Hypoxic neuronal injury in cortical cultures can be attenuated by removal of glutamine, a glutamate precursor, from the culture medium6. (3) Quinolinate, a glutamate analogue that binds the NMDA receptor preferentially, has been found to cause selective cell death in the striatum 7 in a pattern identical to that found in HD patients.
Do adrenergic chromaffin cells exocytose like noradrenergic cells? Three recent reviews in TINS ~-3 attest to the current interest in neuroendocrine secretion. One review pointed out specific differences in secretory processes between pituitary lactrotrophs and adrenal chromaffin cells3 while another implied differences in pancreatic cells~; none questioned whether adrenergic and noradrenergic chromaffin cells, which together constitute the experimental model that is most often chosen for these studies, have the same exocytotic mechanism. Many data, however, document significant differences in the secretory nature of adrenergic and noradrenergic cells4-7. Does the well-known selective liberation of adrenaline and noradrenaline from the adrenal gland in situs result from differential innerration or is it a result of differential modulation of the secretory process in its two principal chromaffin-cell populations? A recent report 9 might shed light on this 440
TrNSVol. 18, No. 10, 1995
question: it showed that the growthassociated protein GAP-43, when introduced experimentally into permeabilized cultured bovine chromaffin cells, acts as a brake to exocytosis by activating a granulebound G protein. Whether GAP-43 is involved in neuroendocrine secretion depends on whether it is present in vivo. Since our initial observation on the expression of GAP-43 in noradrenergic chromaffin cells in the adult adrenal gland ~°, other laboratories tl-13 have also been unable to detect it in adrenergic chromaffin cells. Negative data cannot of course exclude low levels of protein expression but if GAP-43 is active in chromaffin cells, it is more likely to be so in noradrenergic rather than in adrenergic cells. The role of GAP-43 in chromaffin cells, suggested by Vitale and colleagues9, can thus operate only in noradrenergic cells, that is, -20% of chromaffin cells in
(4) Levels of the NMDA receptor are decreased in the striatum of HD patients8, indicating that surviving neurons have few or no NMDA receptors. This evidence, correlated with the recent genetic data that link the neurodegenerative diseases HD, DRPLA, SCAI and MJD, suggests that experimental investigation of a common excitotoxic cellular mechanism of neurodegeneration might increase our understanding of these diseases. It might also point to potential therapies, including alteration of levels of glutamine and glutamate and the use of glutamate-receptor antagonists.
Anthony J. Hannan Developmental Neurobiology Unit, Children's Medical Research Institute, Locked Bag 23, Wentworthville, NSW 2145, Australia. References 1 Albin, R.L. and Tagle, D.A. (1995) Trends Neurosci. 18, 11-14 2 Huntington's Disease Collaborative Research Group (1993) Cell 72, 971-983 3 Koide, R. e t al. (1994) Nat. Genet. 6, 9-13 4 0 l n e y , J.W. and Sharpe, L.G. (1969) Science 166, 386-388 5 Choi, D.W. e t al. (1987) J. Neurosci. 7, 357-368 6 Goldberg, M.P. e t aL (1988) Neurosci. Left. 94, 52-57 7 Beal, M.F. e t al. (1986) Nature 321, 168-171 8 Young, A.B. e t al. (1988) Science 241, 981-983
bovine and rat glands. Adrenergic cells presumably secrete by a different mechanism or use a different protein that fulfils this function. GAP-43 is not the only 'typically' neuronal protein that is downregulated during the noradrenergic-adrenergic transition of chromoblasts. The cell adhesion molecule LI, which is probably involved in segregating noradrenergic from adrenergic cells during adrenal-gland histogenesis, is also undetectable in adrenergic cells t4. Reasons for such differences, and the differential expression of other proteins ~s'~6are, for the moment, obscure but might be related to the low levels of expression of glucocorticoid receptors in noradrenergic cells ~7. A search for genetic differences between the two principal phenotypes of catecholamine-containing chromaffin cells might provide explanations for these differences in both protein expression and secretory mechanisms. References 1 Blondel, O., Bell, G.I. and Seino, S. (1995) Trends Neurosci. 18, 157-161 2 Burgoyne, R.D. and Morgan, A. (1995) Trends Neurosci. 18, 191-196 3 Liedo, J-M. e t aL (1994) Trends Neurosci. 17, 426-432 4 Marley, P.D. and Livett, B.G. (1987)
LETTERS TO THE EDITOR Neurosci. Lett. 77, 81-86 5 Teraoka, H., Sugawara, T. a n d Nakazato, Y. (1993) I. Neurochem. 60, 1936-1940 6 Cahill, A.L. and Perlman, R.L. (1992) J. Neurochem. 58, 768-771 7 Choi, A.Y., Fukui, H. and Perlman, R.L. (1995) J. Neurochem. 64, 206-212 8 Feuerstein, G. a n d G u t m a n , Y. (1971) Br. I. Pharmacol. 43, 764-775 9 Vitale, N. e t al. (1994) J. Biol. Chem.
269, 30293-30298
10 Grant, N.J. et al. (1992) Eur. J. Neurosci. 4, 1257-1263 11 Lopez Costa, J.J. e t al. (1994) Cell Tissue Res. 275, 555-556 12 Holgert, H. et al. (1994) Dev. Brain Res. 83, 35-52 13 Dorsey, D.A. and Schmidt, R.E. (1993) Neurosci. Lett. 162, 29-33 14 Leon, C. et al. (1992) Eur. J. Neurosci. 4, 201-209
15 Happola, O. et al. (1985) Brain Res. 339, 393-396 16 Schultzberg, M. et al. (1989) Neuroscience 30, 805-810 17 Ceccatelli, S. e t al. (1989) Acta Physiol. Scand. 137, 559-560
Keith Langley and Nancy J. Grant INSERM, Unit6 338, 5 rue Blaise-Pascal, F-67084 Strasbourg cedex, France.
Do muscle-spindle afferents act as interneurons during mastication?
Rostral ,,,, ,,,,
II-_-~im - - I
Recently, Wall ~ discussed the active control of propagation through sensory afferents. In addition to primary-afferent depolarization (PAD) of synaptic regions, Wall presented evidence for a new form of GABA-mediated presynaptic control that blocks propagation at some distance from the terminals. We propose that these two mechanisms might be used to convert part of the axonal trees of trigeminal musclespindle afferents into premotor interneurons during mastication. When PAD is strong, it generates antidromic action potentials that propagate into peripheral nerves. It has long been assumed that the function of such antidromic firing is to decrease sensory inputs by colliding with orthodromic spikes2. However, when muscle-spindle afferents fire antidromically, motoneurons are excited 2, presumably because spikes that propagate toward the periphery from depolarized terminals also travel orthodromically down the branches to motoneurons. Bursts of antidromic potentials in sensory axons occur during several rhythmical motor patterns in paralysed animals (fictive movements), suggesting that sensory terminals are depolarized phasically by central pattern generators 3-6 (CPG). Axons of masseter muscle-spindle afferents, recorded caudal to the Vth motor nucleus during fictive mastication show bursts of what appear to be antidromic spikes in phase with activity in masseter motoneurons (jaw closure) (Fig.). During the opposite phase of the cycle, orthodromic spikes from the muscle fail to reach this part of the axon 7. The pattern of antidromic bursts7, and the subgroup of CPG interneurons that are active, change together with the pattern of fictive mastication8, suggesting that PAD might be switched between sets of terminals. In the rostral parts of the neuron, spikes pass during jaw closure, but at the same low frequency as the orthodromic traffic, suggesting that the antidromic bursts are blocked in jaw closure, while orthodromic spikes fail in the opposite phase9. Thus, transmission into different
regions of the axonal tree seems to be under the selective active control that Wall postulated, perhaps through axo-axonic synapses in a crucial region (shaded box). Coupled with PAD at terminals on subpopulations of neurons in the CPG, this might enable the caudal segment of the primary afferent to act as a lastorder interneuron during mastication, while the disconnected rostral segment transmits the peripheral input mono- and bisynaptically to provide phasic servoassistance during jaw closure.
III III IIIIIIIIIIIII
~
'mI~
~
III IIII IIII IIII RI III IIII/ I1[I IIII [11
Motoneurons
A. Kolta J.P. Lund Facult~ de m6decine dentaire, Universit6 de Montr6al, C.P. 6128, succ. Centre-ville, Montr6al, Qu6bec, Canada H3C 3J7.
Myotatic-reflex interneurons
1
" ,,, IIII ,,,, IIII ,,r III ,,, ',',11 I1[I
........... t uron ~!~ups
K-G. Westberg Dept Physiology, University of Ume& S-901 87 Ume&, Sweden. P. Clavelou H6pital Fontmaure and Dept of Neurology, Centre H6pital et Universit6 de Clermont-ferraud, Chamali6res 63400, France. References 1 Wall, P.D. (1995) Trends Neurosci. 18, 99-103 2 Eccles, J.C., Kozac, W. and Magni, F. (1961) J. Physiol• 159, 128-146 3 Baev, K.V. (1978) Neurophysiology 10, 316-317 4 Dubuc, R. e t aL (1985) Brain Res. 359,
375-378 5 Richter, D.W. e t al. (1986) Pfl#gers Arch• 406, 12-19 6 Gossard, J-P. e t aL (1989) J. Neurophysiol. 62, 1177-1189
Caudal Fig. Diagram of a masseter spindle afferent and its connections. These neurons have cell bodies in the Vth mesencephalic nucleus, and a long descending axon that gives off branches at many levels1°. The incoming action potentials that are caused by tonic muscle stretch are shown (1), together with the patterns of firing that are recorded near the soma (2), and the subnucleus oralis (3) during fictive mastication. Note that the bursts in 3 occur in jaw closure, in phase with the motoneurons (4). We suggest that neurons of the central pattern generator (CPG) control the caudal terminals and transmission through the area that is indicated by the shaded box. 7 Clavelou, P. e t al. (1994) Soc. Neurosci. Abstr. 20, 1758 8 Westberg, K-G. e t al. (1994) Soc. Neurosci. Abstr. 20, 1758 9 Kolta, A. e t al. (1990) J. NeurophysioL 64, 1067-1076 10 Shigenaga, Y. e t al. (1988) Brain Res. 445, 392-399
Corrigendum In the article by R. Suzanne Zukin and Michael V.L. Bennett in the July issue of TINS (Vol. 18, pp. 306-313), the referencing of the Table in Box I was incorrect. References a, b, c, d, e and f, identifying the sources of alternative nomenclatures of NRI-receptor splice variants, should be b, c, cl, e, f and g, respectively. We apologise to the authors and to the readers for this error.
TINS VoI. 18, No. 10, 1995
441