Signalling pathways in the brain: Cellular transduction of mood stabilisation in the treatment of manic-depressive illness

Abstract

The long-term treatment of manic-depressive illness (MDI) likely involves the strategic regulation of signalling pathways and gene expression in critical neuronal circuits. Accumulated evidence has identified signalling pathways, in particular the family of protein kinase C (PKC) isozymes, as targets for the long-term action of lithium. Chronic lithium administration produces a reduction in the expression of PKC alpha and epsilon, as well as a major PKC substrate, MARCKS, which has been implicated in long-term neuroplastic events in the developing and adult brain. More recently, studies have demonstrated robust effects of lithium on another kinase system, GSK-3beta, and on neuroprotective/neurotrophic proteins in the brain. Given the key roles of these signalling cascades in the amplification and integration of signals in the central nervous system, these findings have clear implications not only for research into the neurobiology of MDI, but also for the future development of novel and innovative treatment strategies.

Chronic Lithium Treatment Attenuates Intracellular Calcium Mobilization

“…Disturbances of intracellular Ca 2 þ signaling can critically affect cellular function due to calcium's essential role in vital cellular processes including gene expression (Ghosh and Greenberg, 1995), neurogenesis and plasticity (Mattson, 2000), and cell death (Szalai et al, 1999). It is of some interest then that lithium acts on several second messenger systems and intracellular signal transducing proteins (Manji et al, 1999;Williams and Harwood, 2000) that are involved in key cellular functions that affect neurogenesis, neuroplasticity, and cell death (Manji et al, 2000).…”

Structural Effects and Neurofunctional Sequelae of Developmental Exposure to Psychotherapeutic Drugs: Experimental and Clinical Aspects

“…Both the adenylate cyclase and phosphoinositide second messenger systems are deeply influenced by lithium, albeit in different manners, including actions on G proteins and protein kinase C (Jope, 1999;Manji et al, 1999). Evidence that lithium inhibits inositol monophosphatase, decreases brain inositol concentrations, and reduces inositol 1,4,5-triphosphate accumulation in rodent cerebral cortex has led to the inositol depletion hypothesis of its mechanism of action.…”

Genetic tests of biologic systems in affective disorders

“…28 Calcium signaling is closely linked to the phosphoinositide pathway, and expression of protein kinase C subtypes (PRKCA and PRKCE) and its substrate myristoylated alanine-rich protein kinase C (MARCKS) are reduced in the rat brain after chronic treatment with lithium. 29 Monoamine neurotransmitter receptors, such as alpha2 and beta-1-adrenergic receptors, are coupled to G proteins, which, upon stimulation, activate enzymes in the cAMP-signaling pathway. The gene for regulator of G-protein signaling 4 (RGS4) was initially brought into attention by a microarray study and recently reported to be associated with schizophrenia.…”