Regulation of Gene Expression by Lithium and Depletion of Inositol in Slices of Adult Rat Cortex

Abstract

of action of lithium in BD, and these have been re-Sethu Sankaranarayanan, 1 Adam J. Simon, 1 viewed (Gould et al., 2004; Gurvich and Klein, 2002). and Edward M. Scolnick 3 Glycogen synthase kinase 3 (GSK3) and inositol mono-1 Merck & Co., Inc. phosphatase (IMPase) are both inhibited by lithium and West Point, Pennsylvania 19486 have been topics of considerable study as potential 2 Rosetta Inpharmatics LLC, a wholly owned therapeutic targets in BD. subsidiary of Merck & Co. Inc. An effect of lithium on brain inositol levels was dem-401 Terry Avenue North onstrated more then 30 years ago (Allison and Stewart, Seattle, Washington 98011 1971). Inositol phosphates and inositol-containing phospholipids (phosphoinositides) constitute an array of cell signaling molecules with diverse functions (Irvine and Summary Schell, 2001; Majerus, 1992). Most notably, activation of cell surface receptors can activate hydrolysis of Lithium inhibits inositol monophosphatase at theraphosphatidylinositol-4,5-bisphosphate (PIP 2 ) by phospeutically effective concentrations, and it has been pholipase C (PLC) to produce inositol-1,4,5-trisphoshypothesized that depletion of brain inositol levels is phate (IP 3 ), which is a second-messenger molecule. IP 3 an important chemical alteration for lithium's therabinds to its cognate receptor to trigger release of Ca 2+ peutic efficacy in bipolar disorder. We have employed from the endoplasmic reticulum (ER) and a host of adult rat cortical slices as a model to investigate the downstream signaling events. Lithium inhibits two engene regulatory consequences of inositol depletion zymes in the inositol pathway, namely inositol polyeffected by lithium using cytidine diphosphoryl-diacylphosphate 1-phosphatase and IMPase, both uncomglycerol as a functionally relevant biochemical marker petitively with respect to substrate (Majerus, 1992). to define treatment conditions. Genes coding for the Indeed, therapeutically relevant doses of lithium cause neuropeptide hormone pituitary adenylate cyclase acaccumulation of inositol phosphates in the brains of tivating polypeptide (PACAP) and the enzyme that rats and mice (Atack et al., 1992; Sherman et al., 1986). processes PACAP's precursor to the mature form, The "inositol depletion" hypothesis of lithium's action in peptidylglycine ␣-amidating monooxygenase, were BD was formulated by Berridge (Berridge et al., 1989). upregulated by inositol depletion. Previous work has Simply put, lithium blocks IMPase and the recycling of shown that PACAP can increase tyrosine hydroxylase inositol into inositol lipids. This leads to a reduction in (TH) activity and dopamine release, and we found that PIP 2 and a reduction in the ability of the cell (neuron) to the gene for GTP cyclohydrolase, which effectively respond to a stimulus by making IP 3 to stimulate an regulates TH through synthesis of tetrahydrobiopincrease in intracellular Ca 2+ concentration. Thus, neuterin, was also upregulated by inositol depletion. We ronal excitability is reduced, and this somehow leads propos...

Lithium regulates adult hippocampal progenitor development through canonical Wnt pathway activation

“…Alternatively, high lithium levels may be selectively toxic to newborn adult neurons, possibly through its known inhibition of enzymes critical to energy metabolism and nucleoside processing. 15,16,44 This would be consistent with the general finding that adult neurons are more susceptible to both toxic and energy deprivationtype insults than either adult glia or embryonic neurons.…”

A polymorphism of the GTP-cyclohydrolase I feedback regulator gene alters transcriptional activity and may affect response to SSRI antidepressants

“…[6][7][8][9][10] Several pharmacogenomic studies investigating mood-regulating drugs have shown altered expression in several components of the BH 4 pathway. [11][12][13] Together, this evidence supports a link between the BH 4 pathway and mood control, as well as in antidepressant function. Because BH 4 is essential for such important biological systems, the regulation of the enzyme which is rate limiting for BH 4 synthesis, GTP cyclohydrolase I (GTPCH; Figure 1), could be biologically, pathologically and therapeutically important.…”

Region-specific transcriptional changes following the three antidepressant treatments electro convulsive therapy, sleep deprivation and fluoxetine

“…Lithium inhibits inositol monophosphatase and downstream GSK3beta at therapeutically effective concentrations, and it has been hypothesized that depletion of brain inositol levels is an important neurochemical change forming the molecular basis of lithium's therapeutic efficacy in bipolar disorder. 106 GPR88 is upregulated by methamphetamine and valproate, a clinically effective drug in treatment of bipolar disorders, in mouse pharmacogenomic models for bipolar disorders. 37 GPR88 expression on the transcriptional level is lower in BDNF-deficient mice.…”