A large body of evidence indicates that there are abnormalities in serotonin (5-HT) receptor subtypes in the postmortem brains of people who have committed suicide. Several studies of postmortem brain samples have indicated high numbers of 5-HT
2A receptors in the prefrontal cortex of suicide subjects, although this finding has not been replicated in some other studies (see reference
1 for review). 5-HT
2A receptors are linked to the phosphoinositide signaling system, and in the phosphoinositide signaling pathway, agonist-induced activation of 5-HT
2A receptors causes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP
2) by the enzyme phosphoinositide-specific phospholipase C (PI-PLC), which results in the formation of two second messengers: diacylglycerol and inositol 1,4,5-trisphosphate. Diacylglycerol activates protein kinase C and increases the affinity of the enzyme for calcium
(2).
Since some evidence suggests that persistent activation and overactivity of receptors linked to the phosphoinositide signaling system may cause changes in other components of the signaling system, it is possible that G proteins, PLC, and/or protein kinase C may also be abnormal in postmortem brains of suicide subjects. For example, Pacheco et al.
(3) and Cowburn et al.
(4) have shown that there are abnormalities in G protein levels in postmortem brains of suicide subjects. On the other hand, Friedman and Wang
(5), Young et al.
(6), and Mathews et al.
(7) showed abnormal levels of G proteins in postmortem brains of patients with bipolar disorder.
Suicide by teenagers is a major public health concern, and little is known about its neurobiology. The neurobiology of suicide by teenagers may be different from that of suicide by adults, since the observations of many investigators indicate that response to antidepressant treatment, especially to the tricyclics, differs between adolescents and adults with depression
(8,
9). Because there have been so few neurobiological studies in adolescent suicide subjects, it is not clear whether the neurochemical abnormalities observed in adults are also present in teenage suicide subjects.
DISCUSSION
We found that in both membrane and cytosol fractions of the prefrontal cortex, PI-PLC activity and expression of a specific PLC isozyme (PLC β1) were significantly lower in teenage suicide subjects than in normal teenage subjects. Moreover, PI-PLC activity was significantly correlated with the PLC β1 isozyme level in the prefrontal cortex of the teenage suicide subjects. PI-PLC activity and the PLC β1 isozyme level were significantly lower than normal in both the suicide subjects with and without a history of mental disorder, but there were no significant differences in either measure between these subgroups.
We also examined the effect of antidepressant treatment on PI-PLC activity and on expression of the PLC β1 isozyme. Two of the suicide subjects had a history of treatment with antidepressants, but their PI-PLC activity and PLC β1 expression were similar to the mean values of the entire suicide group; however, one subject who had been treated with verapamil expressed a very low level of PLC β1.
Thus, overall our study suggests that adolescents who commit suicide have significantly lower than normal PI-PLC activity in the prefrontal cortex and that this low level is due to selectively lower protein expression of the PLC β1 isozyme. Moreover, these results also suggest that the low PI-PLC activity and expression of the PLC β1 isozyme in suicide subjects is independent of a history of mental illness.
There have been some studies of PI-PLC in postmortem brains of adult suicide subjects. For example, Jope et al.
(17) did not find any significant abnormalities in Ca
2+-stimulated PI-PLC activity in postmortem brain tissue obtained from adult bipolar patients. Pacheco et al.
(3) studied PI-PLC activity and the expression of the PLC β
1 isozyme in postmortem brains of depressed adult suicide subjects but did not observe any significant abnormalities in PI-PLC activity or in PLC β
1 immunolabeling in prefrontal or occipital cortical areas. In a recent publication, Mathews et al.
(7) reported a nonsignificantly higher than normal level of the PLC β
1 isozyme in the occipital cortex, but not the frontal or temporal cortex, of bipolar subjects.
Thus, our finding of low PI-PLC activity and a low level of the PLC β1 isozyme in the postmortem brains of teenage suicide subjects is noteworthy. The reason that PLC β1 expression is abnormal in teenage but not adult suicide subjects is unclear, but it may be that neurobiological factors and clinical characteristics differ between adults and teenagers.
Even though serotonergic mechanisms have not been studied in postmortem brain samples obtained from depressed or suicidal youths or adolescents, the results of several studies suggest the presence of abnormal 5-HT mechanisms in depressed adolescents. Some investigators have reported that CSF 5-hydroxyindoleacetic acid is strongly correlated with aggression in adolescent subjects
(18). Ryan et al.
(19) reported abnormal prolactin and cortisol response to 5-hydroxytryptophan in depressed children, although they did not find any correlation with aggression or suicidality. It has also been reported that depressed children and adolescents have low numbers of platelet serotonin transporter sites
(20,
21) and that these low numbers are associated with suicidality
(21). Neurodevelopmental studies suggest that, whereas the serotonergic system is fully developed in adolescents, the noradrenergic system does not develop fully until early adulthood
(22), and this could be why adolescents are more responsive to selective serotonin reuptake inhibitors than to noradrenergic antidepressants
(9).
The mechanisms associated with the low PI-PLC activity and expression of the PLC β
1 isozyme in teenage suicide are not clear. Since we found low PI-PLC activity and PLC β
1 expression in both membrane and cytosol fractions of brain tissue, it is unlikely that the low PLC values are caused by abnormal translocation of PLC. These low levels do not appear to be related to the postmortem interval or to degradation of PLC enzymes by proteolysis, since the low PLC values were observed in only one of the isozymes, i.e., PLC β
1; however, it is possible that the low PI-PLC activity may be related to a higher number of 5-HT
2A receptors, as has been found in postmortem brains of suicide subjects
(1), which cause stimulation of the phosphoinositide signaling system. It is possible that a sustained increase in phosphoinositide metabolism may cause desensitization of activity in both PLC and protein kinase C and may also cause a decrease in the expression of the PLC β
1 isozyme, to which 5-HT
2A receptors are linked through G
q proteins. There is some evidence in the literature that agonist stimulation of receptors and G proteins can cause desensitization of G proteins and effectors
(23). It has also been observed that agonist stimulation decreases PI-PLC activity in turkey erythrocytes
(24).
Our observations of low PI-PLC activity and expression of PLC β
1, together with our previous report of a low number of [
3H]phorbol dibutyrate binding sites in postmortem brains of teenage suicide subjects
(10), indicate that abnormalities and disturbances in various components of the phosphoinositide signaling system may be associated with the pathophysiology of teenage suicide. Questions remain: Are the abnormalities that are observed downstream in the signaling system related to the abnormalities in the receptors that are linked to the phosphoinositide signaling system or are they independently abnormal? and Do these abnormalities represent genetic vulnerabilities to suicide?