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Schizophrenia: no longer a functional psychosis
TINS- No vember/December 1986
537
Schizophrenia: no longer a functional psychosis Accumulating evidence from the last ten years has demonstrated ihat schizophrenia can no longer be regarded as a functional psychosis but an organic one. Many studies have demonstrated ventricular enlargement in schizophrenia using CT scans, and precise neuroanatomical evidence of brain changes in schizophrenia have now been demonstrated by Crow and his colleagues. The brains of patients with schizophrenia were found to be lighter than those of patients with primary affective disorder; they were also found to have enlarged lateral ventricles, particularly in the temporal horn, and to have significantly thinner parahippocampal cortices. These findings are consistent with abnormalities in neuropeptide concentrations in the temporal lobe (particularly in the amygdala) of schizophrenic patients, and suggests that schizophrenia is a temporal lobe syndrome. Its cause remains elusive but viral infection could be responsible. Since the terms 'dementia praecox' and 'the schizophrenias' were first introduced by Kraepelin 1 and Beuler2, respectively, the argument over the status of schizophrenia as a psychiatric disorder has continued. Kraepelin was convinced that schizophrenia (and indeed, affective psychosis) were diseases of the nervous system in which there was structural brain pathology, but there was little evidence in the ensuing years to back up these claims. More attention was paid to the psychological manifestations of the disorder, and opinion swung gradually towards the view that the syndrome was caused by psychological mechanisms solely. This view reached its peak of popularity in the early 1960s when it was explained that patients became schizophrenic in order to escape the 'double-bind' pathology of their 'schizophrenogenic' parents J. However, preliminary evidence that patients with schizophrenia had enlarged cerebral ventricles4 was confirmed with the introduction of computed tomographic (CT) scans5-7. However, CT scans have limitations in determining ventricular enlargement s and are not suitable for studying ventricular size in the temporal horn of the lateral ventricle. Ventricular enlargement is a relatively non-specific finding, and as it has been found in manic and depressed patients 9-1° and in alcohol addiction 11, it might have no special significance in schizophrenia. Additional evidence of specific abnormalities in the temporal lobe of schizophrenic patients has come from biochemical studies, particularly those concerned with neuropeptide function. While studies of neuropeptide concentrations in post-mortem brain tissue are in their infancy, there have been some consistent demonstrations of abnormal concentrations in the limbic system,
and in particular in structures surrounding the inferior horn of lateral ventricle deep in the temporal lobe 12. The first reports 13'14were distinguished by the careful clinical documentation of schizophrenic patients, with psychotic phenomena being rated before death. In these studies, vasoactive intestinal polypeptide (VIP), cholecystokinin (CCK), somatostatin (SOM) and substance P (SP) concentrations were found to be variously abnormal in amygdala, hippocampus and temporal cortex (areas 21 and 22). Abnormalities seemed to be particularly associated with the defect state of chronic schizophrenia, with CCK and SOM concentrations reduced in hippocampus and CCK reduced in amygdala in so called type-2 cases. It is perhaps noteworthy that this sub-syndrome of schizophrenic illness has been linked to an over-representation of ventricular enlargement in CT scans 15. A study at the MRC brain bank (Emson et al., unpublished observations) found amygdala to be the site of several neuropeptide abnormalities. Concentrations of [Met]enkephalin and SP were reduced whereas the concentration of VIP in amygdala was abnormally high - a finding also reported by Ferrier and colleagues13,14. Most of these peptides have intimate anatomical and physiological relationships with dopamine, the neurotransmitter traditionally associated with neurochemical theories for schizophrenic illness. An asymmetrical temporal lobe abnormality in dopamine concentration in post-mortem schizophrenic brain has been reported in the form of abnormally high concentrations of dopamine in the left amygdala in brains of schizophrenic patients 16. Interhemispheric distribution of neuropeptides in schizophrenic illness has not yet been explored, but of the many
brain structures analysed in recent neurochemical studies of both conventional and peptide transmitters in schizophrenia, the temporal lobe emerges as the locus of greatest interest. The strong presumptive evidence for schizophrenia being a disorder of the temporal lobe has been largely confirmed in a recent neuroanatomical study by Crow and colleagues17. They examined the brains of 232 patients who had suffered from schizophrenia or affective psychosis. Patients who showed evidence of Alzheimer's disease or other conditions associated with senile changes such as plaques and neurofibrillary tangles were excluded from the comparison between schizophrenia and affective psychosis. Retrospective diagnostic criteria for schizophrenia or primary affective disorder also excluded many patients. Of the final sample, 41 patients with schizophrenia were compared with 29 patients with affective disorder. The study showed that patients with schizophrenia had brains that were 6% lighter than those with affective psychosis, and had enlarged lateral ventricles that were 19% larger in the anterior horn and 97% larger in the temporal horn than the ventricles of patients with affective psychosis. The schizophrenic patients also had significantly thinner parahippocampal cortices by a margin of 11%. Although these changes were not as large as similar changes in the brains of patients with Alzheimer'stype dementia and Huntington's disease, they were nonetheless highly significant. The third ventricle was also somewhat larger in the schizophrenic patients (12%), but this finding was not significant and is in keeping with similar findings using an ultrasound technique TM. This study represents one of the most careful enquiries into neuroanatomical changes in schizophrenia to date, and great care was taken to include a homogeneous group of patients with schizophrenia and affective psychosis. Examination of the data showed that there was no evidence of a discrete subgroup of patients with large ventricles compared with those with smaller ones. Of special interest was the finding that in affective psychosis the left parahippocampal gyrus was thicker than the right one, while there was no difference found between right and left parahippocampal gyri in the schizophrenic brains. These findings go some way towards supporting the
© 1986, Elsevier Science Publishers B.V., Amsterdam
0378 - 5912/86J$02.00
538 notion that affective psychosis is a disorder of the non-dominant hemisphere 19. This demonstration of gross neuroanatomical changes confirms that schizophrenia can no longer be regarded as a functional psychosis. Much remains to be done to determine the precise reasons for loss of brain tissue in the temporal lobe and its underlying functional implications. It is also necessary to exclude the hypothesis that at least some of the changes found are a consequence of chronic treatment with antipsychotic drugs. Most studies showing ventricular enlargement in schizophrenics involved many patients who had received a considerable quantity of neuroleptic drugs and ECT. In view of the strong evidence that antipsychotic drugs may produce the neurological syndrome, tardive dyskinesia, after prolonged dosage, it is essential to examine the possibility that the apparent structural brain changes of schizophrenia are iatrogenic. However, in a study in which ventricular size was compared in two groups of schizophrenic patients - one that had received virtually no physical treatments and the other that had received more conventional neuroleptic therapy - there was no significant difference between the groups, and the duration of treatment was also unrelated to lateral ventricular size 2°. There is still much work ahead to establish the links between the specific psychopathological abnormalities of schizophrenia and the structural changes in the temporal lobe. For some time it has been known that temporal lobe epilepsy 2t may present with a schizophreniform psychosis, and it seems likely that all schizophrenia-like syndromes have a common structural base. One possible explanation for temporal lobe pathology and dilated cerebral ventricles in schizophrenia is that they they are due to an infection by a virus-like agent 22. This is supported by the high correlation between ventricular dilatation on CT scan and cytomegalovirus antibody titres 23. Neuropathological signs compatible with old infection, such as fibrillary gliosis, have been reported in schizophrenia 24, but the distribution is not confined to the temporal lobe. Whether an infective agent might be responsible for some cases of schizophrenia remains conjectural, but the failure so far to catch a virus 'in the act' may reflect some novel and
T I N S - November~December 1986
elusive characteristics of the infectious agent 25. The factor responsible might be thought of as a 'virogene '26, a nucleic acid sequence endogenous to the human genome which can be vertically transmitted within families and which, under certain circumstances, becomes derepressed to generate pathological change. Selected references 1 Kraepelin, E. (1909) Psychiatrie: ein Lehrbuch far Studierende und Artze, Barth 2 Beuler, E. (1911) Dementia Praecox or the Group of Schizophrenias (Trans J. Zinkin, 1950). International University Press 3 Singer, M. T. and Wynne, L. C. (1965) Arch. Gen. Psychiatr. 12, 210-206 4 Jacobi, W. and Winkler, H. (1927) Arch. Psychiatr. Nervenkr. 81,299-332 5 Johnstone, E. C., Crow, T. J., Frith, C. D., Husband, J. and Kreel, L. (1976) Lancet ii, 924-926 6 Weinberger, D . R . , Wagner, R . L . and Wyatt, R . J . (1983) Schizophr. Bull. 9, 193-212 Reveley, M.A., 7 Williams, A . O . , Kolakowska, T., Ardern, M. and Mandelbrote, B. M. (1985) Br. J. Psychiatr. 146, 239-246 8 Reveley, M. (1985) Br. J. Psychiatr. 146, 367-371 9 Pearlson, G. D. and Veroff, A. E. (1981) Lancet ii, 470 10 Nasrallah, H. A., Jacoby, C. G., MacCalleyWhiners, M. and Kuperman, S. (1982) J. 11 Affect. Disord. 4, 15-19 Ron, M. A., Acker, W., Shaw, G. K. and Lishman, W. A. (1982) Brain 105,497-514 12 Bisette, G.,Nemeroff, C.B. and Mackay, A. V.P. in Peptides and Neurological Disease: Progress in Brain Research, Vol. 66 (Emson, P. C., Rossor, M. and Tohyama, M., eds), Elsevier, (in press)
13 Roberts, G . W . , Ferrier, I . N . , Lee, Y., Crow, T.J., Johnstone, E . C . , Owens, D. G . C . , Bacarese-Hamilton, A.J., McGregor, G., O'Shaughnessey, D., Polak, J. M. and Bloom, S. R. (1983) Brain Res. 288, 199-211 14 Ferrier, 1. N., Roberts, G. W., Crow, T. J., Johnstone, E. C., Owens, D. G. C., Lee, Y., O'Shaughnessey, D., Adrian, T . E . , Polak, J. M. and Bloom, S. R. (t983) Life Sci. 33. 475~482 15 Andreasen, N. C., Olsen, S. A., Dennert, J . W . and Smith, M . R . (1982) Am. J Psychiatr. 139, 297-302 16 Reynolds, G. P. (1983) Nature 305,527-529 17 Brown, R., Colter, N., Corsellis, J. A. N , Crow, T.J.. Frith, C . D . , Jagoe, R., Johnstone, E. C. and Marsh, L (1986) Arch. Gen. Psyehiatr. 43, 36~-2 18 Bankier, R. G. (1985) Br. J. Psychiatr. t47~ 241-245 19 Flor-Henry, P. and Koles, Z. J. (1980) Adv. Biol. Psychiatr. 4, 21-43 20 Owens, D. G. C., Johnstone, E. C., Crow. T. J., Frith, C. D., Jagoe, J. R. and Kreel, L. (1985) Psychol. Med 15, 27-41 21 Slater, E., Beard, A. W. and Glithero, E. (1963) Br. J. Psychiatr. 10, 95-150 22 Crow, T. J. (1983) Lancet i, 173--175 23 Kaufmann, C . A . , Weinberger, D . R . . Yolken, R. H., Torrey, E. F. and Potkin, S. G. (1983) Lancet, ii, 1136-1137 24 Stevens. I R. (1982) Psychol. Med. 12, 695-71X) 25 Johnson. R. T. (1982) Trends Neurosci. 5. 415~15 26 Baker, H. F., Ridley, R. M. and Crow, T. J. t1985) Br. Med. J. 291,299-302
PETER TYRER AND ANGUS MACKAY* Mapperley Hospital, Porchester Road, Nottingham NG3 6AA, UK and *Argyll & Bute Hospital, Lochgilphead, Argyll PA31 8LD, UK.
Protein kinase C: a key regulator of neuronal excRablllty? In the 1960s a great deal of excitement followed the discovery of the second messenger cyclic AMP. Analogues of cyclic A M P proved to have a large number of effects on neurones and other types of cells. These observations implicated cyclic A M P in the normal regulation of many cellular functions. Similar excitement and activity has recently been generated from results with tumor-promoting phorbol esters. These substances also have a very large number of effects on the nervous system and other tissues. We know that the mechanism of action of these substances normally involves stimulation of the enzyme protein kinase C (PKC). In this article, I would like to briefly review the properties of PKC
1986.ElsevierSciencePublishersB.V.. Amsterdam 0378 5912/86/$02.0(I
and to illustrate some of its interesting actions associated with the nervous system. Although it is widely distributed in many tissues, particularly high concentrations of PKC appear to exist in the nervous system of both vertebrates and invertebrates 1-3. The major form of the enzyme is about 80 kDa, although other forms may also exist 4. Three major factors are required for activation of the enzyme in vitro: Ca 2÷, phospholipid (particularly ~phosphatidylserine) and diacylglycerol\ It is the effect of diacylglycerol ( D A G ) that can be mimicked by a variety of tumor-promoting drugs such as the phorbol esters and mezerein 5. It is clear that activation of PKC is often associated with the
537
Schizophrenia: no longer a functional psychosis Accumulating evidence from the last ten years has demonstrated ihat schizophrenia can no longer be regarded as a functional psychosis but an organic one. Many studies have demonstrated ventricular enlargement in schizophrenia using CT scans, and precise neuroanatomical evidence of brain changes in schizophrenia have now been demonstrated by Crow and his colleagues. The brains of patients with schizophrenia were found to be lighter than those of patients with primary affective disorder; they were also found to have enlarged lateral ventricles, particularly in the temporal horn, and to have significantly thinner parahippocampal cortices. These findings are consistent with abnormalities in neuropeptide concentrations in the temporal lobe (particularly in the amygdala) of schizophrenic patients, and suggests that schizophrenia is a temporal lobe syndrome. Its cause remains elusive but viral infection could be responsible. Since the terms 'dementia praecox' and 'the schizophrenias' were first introduced by Kraepelin 1 and Beuler2, respectively, the argument over the status of schizophrenia as a psychiatric disorder has continued. Kraepelin was convinced that schizophrenia (and indeed, affective psychosis) were diseases of the nervous system in which there was structural brain pathology, but there was little evidence in the ensuing years to back up these claims. More attention was paid to the psychological manifestations of the disorder, and opinion swung gradually towards the view that the syndrome was caused by psychological mechanisms solely. This view reached its peak of popularity in the early 1960s when it was explained that patients became schizophrenic in order to escape the 'double-bind' pathology of their 'schizophrenogenic' parents J. However, preliminary evidence that patients with schizophrenia had enlarged cerebral ventricles4 was confirmed with the introduction of computed tomographic (CT) scans5-7. However, CT scans have limitations in determining ventricular enlargement s and are not suitable for studying ventricular size in the temporal horn of the lateral ventricle. Ventricular enlargement is a relatively non-specific finding, and as it has been found in manic and depressed patients 9-1° and in alcohol addiction 11, it might have no special significance in schizophrenia. Additional evidence of specific abnormalities in the temporal lobe of schizophrenic patients has come from biochemical studies, particularly those concerned with neuropeptide function. While studies of neuropeptide concentrations in post-mortem brain tissue are in their infancy, there have been some consistent demonstrations of abnormal concentrations in the limbic system,
and in particular in structures surrounding the inferior horn of lateral ventricle deep in the temporal lobe 12. The first reports 13'14were distinguished by the careful clinical documentation of schizophrenic patients, with psychotic phenomena being rated before death. In these studies, vasoactive intestinal polypeptide (VIP), cholecystokinin (CCK), somatostatin (SOM) and substance P (SP) concentrations were found to be variously abnormal in amygdala, hippocampus and temporal cortex (areas 21 and 22). Abnormalities seemed to be particularly associated with the defect state of chronic schizophrenia, with CCK and SOM concentrations reduced in hippocampus and CCK reduced in amygdala in so called type-2 cases. It is perhaps noteworthy that this sub-syndrome of schizophrenic illness has been linked to an over-representation of ventricular enlargement in CT scans 15. A study at the MRC brain bank (Emson et al., unpublished observations) found amygdala to be the site of several neuropeptide abnormalities. Concentrations of [Met]enkephalin and SP were reduced whereas the concentration of VIP in amygdala was abnormally high - a finding also reported by Ferrier and colleagues13,14. Most of these peptides have intimate anatomical and physiological relationships with dopamine, the neurotransmitter traditionally associated with neurochemical theories for schizophrenic illness. An asymmetrical temporal lobe abnormality in dopamine concentration in post-mortem schizophrenic brain has been reported in the form of abnormally high concentrations of dopamine in the left amygdala in brains of schizophrenic patients 16. Interhemispheric distribution of neuropeptides in schizophrenic illness has not yet been explored, but of the many
brain structures analysed in recent neurochemical studies of both conventional and peptide transmitters in schizophrenia, the temporal lobe emerges as the locus of greatest interest. The strong presumptive evidence for schizophrenia being a disorder of the temporal lobe has been largely confirmed in a recent neuroanatomical study by Crow and colleagues17. They examined the brains of 232 patients who had suffered from schizophrenia or affective psychosis. Patients who showed evidence of Alzheimer's disease or other conditions associated with senile changes such as plaques and neurofibrillary tangles were excluded from the comparison between schizophrenia and affective psychosis. Retrospective diagnostic criteria for schizophrenia or primary affective disorder also excluded many patients. Of the final sample, 41 patients with schizophrenia were compared with 29 patients with affective disorder. The study showed that patients with schizophrenia had brains that were 6% lighter than those with affective psychosis, and had enlarged lateral ventricles that were 19% larger in the anterior horn and 97% larger in the temporal horn than the ventricles of patients with affective psychosis. The schizophrenic patients also had significantly thinner parahippocampal cortices by a margin of 11%. Although these changes were not as large as similar changes in the brains of patients with Alzheimer'stype dementia and Huntington's disease, they were nonetheless highly significant. The third ventricle was also somewhat larger in the schizophrenic patients (12%), but this finding was not significant and is in keeping with similar findings using an ultrasound technique TM. This study represents one of the most careful enquiries into neuroanatomical changes in schizophrenia to date, and great care was taken to include a homogeneous group of patients with schizophrenia and affective psychosis. Examination of the data showed that there was no evidence of a discrete subgroup of patients with large ventricles compared with those with smaller ones. Of special interest was the finding that in affective psychosis the left parahippocampal gyrus was thicker than the right one, while there was no difference found between right and left parahippocampal gyri in the schizophrenic brains. These findings go some way towards supporting the
© 1986, Elsevier Science Publishers B.V., Amsterdam
0378 - 5912/86J$02.00
538 notion that affective psychosis is a disorder of the non-dominant hemisphere 19. This demonstration of gross neuroanatomical changes confirms that schizophrenia can no longer be regarded as a functional psychosis. Much remains to be done to determine the precise reasons for loss of brain tissue in the temporal lobe and its underlying functional implications. It is also necessary to exclude the hypothesis that at least some of the changes found are a consequence of chronic treatment with antipsychotic drugs. Most studies showing ventricular enlargement in schizophrenics involved many patients who had received a considerable quantity of neuroleptic drugs and ECT. In view of the strong evidence that antipsychotic drugs may produce the neurological syndrome, tardive dyskinesia, after prolonged dosage, it is essential to examine the possibility that the apparent structural brain changes of schizophrenia are iatrogenic. However, in a study in which ventricular size was compared in two groups of schizophrenic patients - one that had received virtually no physical treatments and the other that had received more conventional neuroleptic therapy - there was no significant difference between the groups, and the duration of treatment was also unrelated to lateral ventricular size 2°. There is still much work ahead to establish the links between the specific psychopathological abnormalities of schizophrenia and the structural changes in the temporal lobe. For some time it has been known that temporal lobe epilepsy 2t may present with a schizophreniform psychosis, and it seems likely that all schizophrenia-like syndromes have a common structural base. One possible explanation for temporal lobe pathology and dilated cerebral ventricles in schizophrenia is that they they are due to an infection by a virus-like agent 22. This is supported by the high correlation between ventricular dilatation on CT scan and cytomegalovirus antibody titres 23. Neuropathological signs compatible with old infection, such as fibrillary gliosis, have been reported in schizophrenia 24, but the distribution is not confined to the temporal lobe. Whether an infective agent might be responsible for some cases of schizophrenia remains conjectural, but the failure so far to catch a virus 'in the act' may reflect some novel and
T I N S - November~December 1986
elusive characteristics of the infectious agent 25. The factor responsible might be thought of as a 'virogene '26, a nucleic acid sequence endogenous to the human genome which can be vertically transmitted within families and which, under certain circumstances, becomes derepressed to generate pathological change. Selected references 1 Kraepelin, E. (1909) Psychiatrie: ein Lehrbuch far Studierende und Artze, Barth 2 Beuler, E. (1911) Dementia Praecox or the Group of Schizophrenias (Trans J. Zinkin, 1950). International University Press 3 Singer, M. T. and Wynne, L. C. (1965) Arch. Gen. Psychiatr. 12, 210-206 4 Jacobi, W. and Winkler, H. (1927) Arch. Psychiatr. Nervenkr. 81,299-332 5 Johnstone, E. C., Crow, T. J., Frith, C. D., Husband, J. and Kreel, L. (1976) Lancet ii, 924-926 6 Weinberger, D . R . , Wagner, R . L . and Wyatt, R . J . (1983) Schizophr. Bull. 9, 193-212 Reveley, M.A., 7 Williams, A . O . , Kolakowska, T., Ardern, M. and Mandelbrote, B. M. (1985) Br. J. Psychiatr. 146, 239-246 8 Reveley, M. (1985) Br. J. Psychiatr. 146, 367-371 9 Pearlson, G. D. and Veroff, A. E. (1981) Lancet ii, 470 10 Nasrallah, H. A., Jacoby, C. G., MacCalleyWhiners, M. and Kuperman, S. (1982) J. 11 Affect. Disord. 4, 15-19 Ron, M. A., Acker, W., Shaw, G. K. and Lishman, W. A. (1982) Brain 105,497-514 12 Bisette, G.,Nemeroff, C.B. and Mackay, A. V.P. in Peptides and Neurological Disease: Progress in Brain Research, Vol. 66 (Emson, P. C., Rossor, M. and Tohyama, M., eds), Elsevier, (in press)
13 Roberts, G . W . , Ferrier, I . N . , Lee, Y., Crow, T.J., Johnstone, E . C . , Owens, D. G . C . , Bacarese-Hamilton, A.J., McGregor, G., O'Shaughnessey, D., Polak, J. M. and Bloom, S. R. (1983) Brain Res. 288, 199-211 14 Ferrier, 1. N., Roberts, G. W., Crow, T. J., Johnstone, E. C., Owens, D. G. C., Lee, Y., O'Shaughnessey, D., Adrian, T . E . , Polak, J. M. and Bloom, S. R. (t983) Life Sci. 33. 475~482 15 Andreasen, N. C., Olsen, S. A., Dennert, J . W . and Smith, M . R . (1982) Am. J Psychiatr. 139, 297-302 16 Reynolds, G. P. (1983) Nature 305,527-529 17 Brown, R., Colter, N., Corsellis, J. A. N , Crow, T.J.. Frith, C . D . , Jagoe, R., Johnstone, E. C. and Marsh, L (1986) Arch. Gen. Psyehiatr. 43, 36~-2 18 Bankier, R. G. (1985) Br. J. Psychiatr. t47~ 241-245 19 Flor-Henry, P. and Koles, Z. J. (1980) Adv. Biol. Psychiatr. 4, 21-43 20 Owens, D. G. C., Johnstone, E. C., Crow. T. J., Frith, C. D., Jagoe, J. R. and Kreel, L. (1985) Psychol. Med 15, 27-41 21 Slater, E., Beard, A. W. and Glithero, E. (1963) Br. J. Psychiatr. 10, 95-150 22 Crow, T. J. (1983) Lancet i, 173--175 23 Kaufmann, C . A . , Weinberger, D . R . . Yolken, R. H., Torrey, E. F. and Potkin, S. G. (1983) Lancet, ii, 1136-1137 24 Stevens. I R. (1982) Psychol. Med. 12, 695-71X) 25 Johnson. R. T. (1982) Trends Neurosci. 5. 415~15 26 Baker, H. F., Ridley, R. M. and Crow, T. J. t1985) Br. Med. J. 291,299-302
PETER TYRER AND ANGUS MACKAY* Mapperley Hospital, Porchester Road, Nottingham NG3 6AA, UK and *Argyll & Bute Hospital, Lochgilphead, Argyll PA31 8LD, UK.
Protein kinase C: a key regulator of neuronal excRablllty? In the 1960s a great deal of excitement followed the discovery of the second messenger cyclic AMP. Analogues of cyclic A M P proved to have a large number of effects on neurones and other types of cells. These observations implicated cyclic A M P in the normal regulation of many cellular functions. Similar excitement and activity has recently been generated from results with tumor-promoting phorbol esters. These substances also have a very large number of effects on the nervous system and other tissues. We know that the mechanism of action of these substances normally involves stimulation of the enzyme protein kinase C (PKC). In this article, I would like to briefly review the properties of PKC
1986.ElsevierSciencePublishersB.V.. Amsterdam 0378 5912/86/$02.0(I
and to illustrate some of its interesting actions associated with the nervous system. Although it is widely distributed in many tissues, particularly high concentrations of PKC appear to exist in the nervous system of both vertebrates and invertebrates 1-3. The major form of the enzyme is about 80 kDa, although other forms may also exist 4. Three major factors are required for activation of the enzyme in vitro: Ca 2÷, phospholipid (particularly ~phosphatidylserine) and diacylglycerol\ It is the effect of diacylglycerol ( D A G ) that can be mimicked by a variety of tumor-promoting drugs such as the phorbol esters and mezerein 5. It is clear that activation of PKC is often associated with the