Synaptic homeostasis and Parkinson's disease

13 Campagnoni, A. T. and Macklin, W. B. (1988) Mol. NeurobioL 2, 41-89 14 Miller, R. D., ffrench-Constant, C. and Raft, M. C. (1989) Annu. Rev. Neurosci. 12, 517-534 15 Raft, M. C., Miller, R. H. and Noble, M. (1986) Nature 303, 390--396 16 Fulton, B. and Raft, M. C. Ann. New YorkAcad. Sci. (in press) 17 ffrench-Constant, C. and Raft, M. C. (1986) Nature 319, 499--502 18 Noble, M. et al. (1990) Philos. Trans. R. Soc. London Set. B 327, 127-143 19 Penfield, W. and Cone, W. (1926) Arch. Neurol. Psychiatr. 16, 130-159 20 Scolding, N. J., Morgan, B. P. and Houston, A. (1989) J. Neurol. Sci. 89, 289-300 21 Hirayama, M., Lisak, R. P. and Silberberg, D. H. (1986) Neurology 36, 276-278 22 Wood, P. M. and Bunge, R. P. (1986)J. NeuroL Sci. 74, 153-169 23 Cyong, C-Y., Witkin, C. S. and Reiger, B. (1982) J. Exp. Med. 155, 587-597 24 Vanguri, P., Koski, C. L. and Silverman, B. (1985) Proc. Nat/ Acad. Sci. USA 79, 3290--3294 25 Wren, D. R. and Noble, M. (1989) Proc. NatlAcad. Sci. USA 86, 9025-9029 26 Mollnes, T. E. and Lachmann, P. J. (1988) Scand. J. Immunol. 27, 127-142 27 Scolding, N. J., Morgan, B. P. and Houston, A. (1989) Nature 339, 620-622 28 Morgan, B. P. (1989) Biochem. J. 264, 1-14 29 Scolding, N. J., Houston, W. A. J. and Morgan, B. P. (1989) Immunology 67, 441-446 30 Scolding, N. J., Jones, J., Compston, D. A. S. and Morgan, B. P. (1990) Immunology 70, 6-10 31 Scolding, N. J., Morgan, B. P. and Frith, S. J. (1990) J. NeuroL Neurosurg. Psychiatry 53, 811 32 Selmaj, K W. and Raine, C. S. (1988) Ann. Neurol. 23, 339-346 33 Cammer, W., Bloom, B. R. and Norton, W. T. (1978) Proc.

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Synaptic homeostasis and Parkinson's disease SIR: The article by Zigmond e t al. ~ in the July issue of last year's TINS offers an attractive explanation for the conventional idea that the emergence of neurological disorders of Parkinson's disease requires an almost complete degeneration of the dopaminergic, nigrostriatal bundle: compensatory events in the residual dopaminergic neurones maintain the control over striatal function and, accordingly, prolong the preclinical phase of this disease. According to the authors, frank clinical abnormalities either reflect a disruption of these compensatory processes or signal a degenerative process that exceeds the limits of compensation. The authors provide a reasonable body of data from work on animals in favour of their hypothesis. However, several interesting points are not taken into account. The article contains t w o basic assumptions that are not explicitly formulated. First, it is assumed 182

Natl Acad. Sci. USA 75, 1554-1558 34 Scolding, N. J. and Compston, D. A. S. (1991) Immunology 72, 127-132 35 Wright, S. D. and Silverstein, S. C. (1986) Handbook of Experimental Immunology (Vol. 2, 4th edn), Blackwell 36 Smith, K. J. and Hall, S. M. (1988) J. Neurol. Sci. 83, 37-53 37 Jans, H., Heltberg, A. and Zeeberg, I. (1984) Acta Neurol. Scand. 69, 34-38 38 Sanders, M. E., Koski, C. L. and Robbins, D. (1986) J. ImmunoL 136, 4456-4459 39 Omlin, F. X., Webster, H. F and Palkovitz, C. G. (1982) J. Cell. BioL 95, 242-248 40 Lightman, S., McDonald, W. I~ and Bird, A. C. (1987) Brain 110, 405-414 41 Simmons, R. D., Buzbec, T. M. and Linthicum, D. S. (1987) Acta Neuropathol. 74, 191-193 42 Wekerle, H. eta/. (1986) Trends Neurosci. 9, 271-277 43 Sedgwick,J., Brostoff, S. and Mason, D. (1987) J. Exp. Med. 165, 1058-1075 44 Vass, K., Lassmann, H. and Wekerle, H. (1986) Acta Neuropathol. 70, 149-160 45 Hayes, M., Woodroofe, M. N. and Cuzner, M. L. (1987) J. Neurol. Sci. 80, 25-37 46 Hayashi, T., Morimoto, C. and Burks, J. S. (1988) Ann. NeuroL 24, 523-531 47 Ben Nun, A., Wekerle, H. and Cohen, I. R. (1981) Eur. J. ImmunoL 11, 195-199 48 Traugott, U., Scheinberg, L. C. and Raine, C. S. (1985) J. NeuroimmunoL 8, 1-14 49 Haffler, D. A., Benjamin, D. S. and Burks, J. (1987) J. Immunol. 139, 89-92 50 Silberberg, D. H., Manning, M. C. and Schreiber,A. P. (1984) Ann. NeuroL 15, 575-580 51 Sergott, R. C., Brown, M. J. and Polenta, R. M. D. (1985) Neurology 35, 1438-1442 52 Blakemore,W., Crang, A. J. and Franklin, R. J. M. Cellular and Molecular Biology of Myelination, Springer-Verlag (in press) 53 Adams, C. W. M,, Poston, M. R. and Buk, S. J. (1985) J. Neurol. Sci. 69, 269-283

that a small dopaminergic deficiency within the striatum does not produce any behavioural deficit. Second, the authors assume that neurological deficits appear as soon as the dopaminergic control over striatal function is lost. Although these assumptions are not in conflict with the outcome of more conventional studies on the basal ganglia 2-5, there is now evidence that they need revision. Concerning the first assumption, there is evidence that even a small dopaminergic deficit within the striatum produces subtle changes in behaviour 6-8, such as a reduced ability to show arbitrary switching of ongoing behaviour this small dopamine deficit is not sufficient to produce pure motor disorders 6'7. This change can be manifested at all levels of behaviour. In humans, such a small deficit is evident at the cognitive level, and is labelled as 'a reduced shifting aptitude '9'1°. Today, there is evidence that these cognitive disorders require a smaller dopamine deficiency than

that required for the occurrence of pure neurological disorders 11. Given that dopamine completion therapy might at least partly ameliorate these cognitive deftcits 12, it appears that the postulated synaptic h o m e o s t a s i s has already broken down. These data indicate that the picture painted by Zigmond et a/. ~ represents an over-simplification and indicates that (1) absence of pure motor disorders does not imply that the postulated homeostasis maintains dopaminergic control over striatal function, (2) that the occurrence of pure motor disorders is certainly not the first sign that the postulated synaptic h o m e o s t a s i s starts to break down and (3) that the postulated synaptic homeostasis is unable to compensate a very small dopamine deficiency within the striatum. Given these findings, it is now worthwhile to consider the assessment of neuropsychological tests as a valid tool to diagnose Parkinson's disease at a very early stage. Since this method is noninvasive, it might be better than TINS, Vo/. 14, No. 5, 1991

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pallidal pathway plays a crucial (1978) Neuropharmacology 12, 665-685 role, is such an important path16 Tassin,J. P. etal. (1979) Neuroscience way 7. 4, 1569-1582 Concerning the second asTo sum up, we feel that the sumption, it is now evident that a above points have far-reaching dopaminergic deficit within the consequences. First, we can no striatum results only in pure longer justify limiting ourselves to Reply motor disorders when the deficit frank neurological disorders when SIR: is so large that hierarchically low- discussing the aetiology of Par- In our recent TINS article 1, we er order output stations, such as kinson's disease. Second, it is no summarized our hypothesis that the substantia nigra, pars reticu- longer justified to draw sharp after partial loss of dopaminelata and the deeper layers of borderlines between symptoms containing neurons within the nigrostriatal pathway compensathe superior colliculus, begin to characteristic of the preclinical dysfunction 7'13. Thus, the overt and clinical phase of this disease. tory events serve to maintain a neurological disorders appear Finally, it is wrong to assume that considerable degree of doponly when output stations of the disruption of the postulated aminergic control over striatal striatum start to dysfunction, but synaptic homeostasis results only function, thus precluding gross not when the striatum dysfunc- in neurological disorders: it also behavioral deficits except under unusual circumstances. In his tions as a result of the disruption results in more subtle programmof the postulated synaptic ing disorders that manifest them- letter, Prof. Cools correctly calls homeostasisT: in the latter case, selves at the cognitive and motor attention to instances where our presentation was incomplete and only subtle programming dis- levels. orders of behaviour described Alexander Rudolf Cools we are grateful for the opporabove appear. One of the most Department of Pharmacology, University of tunity to deal with those instances important consequences of this is Nijmegan, PO Box 9101, 6500 lib Nijmegan, here. As Cools notes, we did not that the output stations of the The Netherlands. discuss the full range of comstriatum might already be dyspensatory events that might functioning when the diagnosis of Selectedreferences 1 ZJgmond, M. J., Abercrombie, E. D., occur in response to damage to Parkinson's disease is made. This Berger, T. W., Grace, A. A. and nigrostriatal dopamine neurons. has the important implication that Stricker, E.M. (1990) Trends Neurosci. Whereas we emphasized locally experiments, such as striatal 13,290-296 manipulations by fetal tissue 2 Bernheimer, H., Birkmayer, W., initiated changes in dopamine transplants, will provide misleadHornykiewicz, O., Jellinger, K. and availability, he suggests other Seitelberger, F. (1973) J. Neurol. Sci. possibilities: (1)increases in the ing results as long as the analysis 20, 415-455 firing rates of residual dopamine is limited to changes in motor 3 Hornykiewicz, O. (1966) Pharmacol. neurons; (2) the growth of new behaviour. Subtle programming Rev, 18, 925-964 disorders characteristic of a dys4 McGeer, P. L. and McGeer, E. G. dopamine terminal axons and (3) (1978) in Parkinson's Disease II (Finch, changes at other sites, including functioning striatum are then C. E., Potter, D. E. and Maletta,A. D., sites downstream from the dopoverlooked. eds), pp. 41-57, Plenum Press aminergic input and pathways A third issue involves the 5 Ranje, C. and Ungerstedt, U. (1977) that bypass the striatum entirely. nature of the compensatory proBrain Res. 134, 83-93 cesses that maintain homeostasis. 6 Cools,A. R. (1980) Behav. Brain Res. To this list we might add several 1,361-378 other possibilities, including (4) Although synaptic homeostasis 7 Cools,A. R. etal. (1984) in The Basal changes in the sensitivity of the can indeed play an important Ganglia (McKenzie,J. S., Kemm, R. E. role 1, it is not the only compenand Wilcock, L. N., eds),pp. 513-544, postsynaptic target and (5) behavioral adaptations. satory mechanism that prevents Plenum Press We have long held that each of 8 Spirduso, W. W. et al. (1985) Brain the emergence of cognitive and Res. 335, 45-54 these processes must be conneurological disorders. Enhance9 Brown, R, G. and Marsden, C. D. sidered when developing a model ment of the firing rate of the (1988) Brain 111,323-345 residual dopaminergic neurons as 10 Cools,A. R., van den Bercken,J. H. L., of recovery of function after para consequence of the reduced Horstink, M. W. I., van Spaendonck, tial injury to both central and K. P. M. and Berger, H. J. C. (1984) peripheral monoaminergic pathactivity of striatal efferents that J. NeuroL Neurosurg. Psychiatr. 47, ways (see Refs 2, 3 for more impinge upon the dopaminergic 443-453 cell bodies 14 ' 15 and sprouting of 11 Berger, H. J. C. etal. (1989) Neuro- extended discussions). However, dopaminergic collaterals ~6 are the evidence that such changes psychologia 27, 629--639 also mechanisms that can main- 12 Downes, J. J. et aL (1989) Neuro- actually occur after the type of psychologia 27, 1329-1343 tain this type of homeostasis. brain injury on which our article Apart from these, changes in the 13 Gelissen, M. and Cools, A. R. focuses is meager and in some (1988) Behav. Brain. Res. 27, activity of neuronal pathways cases non-existent. For example, 205-214 that bypass the affected striatum 14 Carlsson,A., Kehr, W. and Linclqvist, the firing rate of dopamine cells in M. (1975) Excerpta Medica Int. substantia nigra does not appear can also compensate the beCongress (Seriesno. 359) (Boissier,J., to increase after partial lesions, at havioural consequences of a dopHippius, H. and Pichot, P., eds), pp. aminergic deficiency within the least not until lesions are excep468-471, ExcerptaMedica striatum. The mesolimbic cir- 15 Schwarz,J. C., Costentin,J., Martres, tionally large. This observation, cuitry, in which the accumbensM. P., Protais, P. and Bauclry, M. briefly outlined in our review, has the diagnostic pharmacological probes suggested by Zigmond et a/. 1

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