Ameliorating prefrontal cortical dysfunction in mental illness: inhibition of phosphotidyl inositol-protein kinase C signaling

Bipolar disorder and schizophrenia are associated with profound dysfunction of the prefrontal cortex (PFC), with bipolar disorder most associated with changes in ventromedial PFC and schizophrenia more associated with changes in dorsolateral PFC. Recent genetic and biochemical studies have also linked these illnesses to disinhibition of phosphotidyl inositol-protein kinase C signaling. For example, DAG kinase eta, an enzyme that metabolizes DAG and thus reduces protein kinase C activity, is the gene most altered in bipolar disorder. Similarly, regulator of G protein signaling 4 is the molecule most altered in the PFC of patients with schizophrenia, and this molecule normally serves to inhibit Gq signaling. Animal studies have shown that high levels of phosphotidyl inositol-protein kinase C signaling in the PFC markedly impair PFC function at the behavioral and cellular levels. Most importantly, many effective medications for bipolar disorder and schizophrenia inhibit phosphotidyl inositol-protein kinase C signaling, either through intracellular actions (lithium, valproate) or through extracellular blockade of receptors coupled to this pathway (5HT2 receptors and alpha-1 adrenoceptors). Recent data suggest that lithium and valproate can protect gray matter in patients with bipolar disorder. These findings encourage the development of protein kinase C inhibitors for the treatment of mental illness.