Postmortem Brain Studies

Significantly higher levels of Gaq/11 and a moderate elevation in the Gaq/11-regulated phospholipase C-P1 isozyme (PLC-P1) have been reported in the occipital cortex of BD subjects compared with matched controls (78). The increases in Gaq/11 and PLC-P1 appeared to be regionally specific, as no significant differences were found between BD and control subjects in the cerebral frontal and temporal cortex (15,78). In addition, Gaq/11 levels, expressed as a percent of respective postmortem delay and age-matched controls, correlated significantly with PLC-P1 values in occipital cortex but not in the other regions examined (78).

Parallel studies of Gaq/11 functional activity, as revealed by GTPyS-stimu-lated [3H]phosphatidylinositol (PI) hydrolysis, indicated a selective decrease in this response in the BD occipital cortex but not other cortical regions (79). Because NaF-stimulated [3H]PI hydrolysis was not different in the BD occipital cortex, it has been suggested that the function of Gaq/11 may be impaired at the level of GDP-GTP exchange (79). Furthermore, the functional impairment of Gaq/11 signaling activity may lead to compensatory changes (i.e., enhanced synthesis and/or stability of the mRNA encoding these a-subunits), resulting in the higher Gaq/11 levels observed in BD occipital cortex (78).

The reciprocal changes in the levels and activity of Gaq/11 in BD occipital cortex also appear to uniquely distinguish this disorder from Alzheimer's disease (79a), schizophrenia (44), alcoholism (44), and major depression (80), in which the activity of Gaq/11 is either increased or decreased in the absence of changes in Gaq/11 and PLC-P1levels. It is also noteworthy that the largest differences in Gas levels and forskolin-stimulated adenylyl cyclase activity were observed in the occipital cortex of BD subjects (10,11). Given the substantial evidence of crossregulation between cAMP and PPI signaling pathways, the possibility that the observed differences in Gaq/11 and PLC-p1 levels may reflect the consequences of relatively greater disturbances in cAMP signaling in this brain region in BD cannot be excluded.

Dysregulation of Gaq/11 levels and activity in BD patients may have important downstream effects in the PPI signaling cascade. This notion is supported by preliminary findings of higher basal membrane protein kinase C (PKC) activity and greater stimulus-induced redistribution of the enzymes in autopsied BD frontal cortex compared with matched controls (81). Furthermore, the levels of cytosolic PKC-a and membrane-associated PKC-y and PKC-Z isozymes were elevated, whereas cytosolic PKC-e was reduced in the BD frontal cortex. The above results, taken together, strongly implicate disturbances in Gaq/11-mediated PPI signaling as playing a role in the pathophysiology of BD.

Postmortem investigations of myo-inositol levels and inositol monophosphate phosphomonoesterase (IMPase) activity in BD (82) have yielded little promising data in support of altered PPI signaling in BD, unfortunately. Furthermore, reduced myo-inositol levels were also found in depressed suicide subjects, suggesting these changes are not specific to BD. Although myo-inositol levels may regulate phospholipase C activity (83), the pathophysiological relevance of lower myo-inositol levels in the postmortem BD frontal cortex (82) remains to be determined.

Clinical Studies

Although no significant differences in the Gaq/11 levels have been found in platelets and leukocytes from BD subjects compared with matched controls (62), other findings from studies of platelets do implicate abnormalities in the PPI signaling pathway in these cells in BD. Brown and co-workers (84) reported significantly higher platelet membrane phosphatidyl inositol 4,5-bisphosphate (PIP2) concentrations in drug-free bipolar manic patients compared with healthy controls. In addition, platelet membrane PKC activity was significantly increased in unmedicated bipolar manic patients compared with healthy individuals (85). Interestingly, the elevated PIP2 levels and PKC activity in the manic state were both normalized following lithium therapy (85,86), suggesting that the hyperactive PPI signaling pathway in BD represents another important target of lithium action in treating this disorder. It is not clear, however, whether these PPI signaling abnormalities arise de novo or are a consequence of disturbances in the Ca2+ and/or cAMP signal transduction systems through crossregulation.

Of interest from a therapeutic perspective, significantly lower IMPase activity has been found in immortalized lymphoblastoid cell lines derived from BD patients responsive to lithium therapy compared with either lithium nonresponsive BD patients or healthy controls (87). In lymphoblastoid cell lines treated chronically with lithium, IMPase mRNA levels were significantly increased. These results suggest that in lithium-responsive BD patients who exhibit trait-dependent low IMPase activity, the transcriptional upreg-ulation of IMPase mRNA levels by lithium may normalize IMPase enzyme levels and activity (87). Such evidence further supports the idea that the effect of lithium on PPI signaling is at least one important component of its molecular actions, which accounts for its therapeutic efficacy in BD.

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