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Neuron DOI:10.1016/j.neuron.2005.02.006

Regulation of gene expression by lithium and depletion of inositol in slices of adult rat cortex.

Publication TypeJournal Article
Year of Publication2005
AuthorsBrandish, PE, Su, M, Holder, DJ, Hodor, P, Szumiloski, J, Kleinhanz, RR, Forbes, JE, McWhorter, ME, Duenwald, SJ, Parrish, ML, Na, S, Liu, Y, Phillips, RL, Renger, JJ, Sankaranarayanan, S, Simon, AJ, Scolnick, EM
Date Published2005 Mar 24
KeywordsAnimals, Antimanic Agents, Biomarkers, Biopterin, Bipolar Disorder, Cerebral Cortex, Cytidine Diphosphate Diglycerides, Down-Regulation, Gene Expression Profiling, Gene Expression Regulation, GTP Cyclohydrolase, Inositol, Lithium Chloride, Male, Mixed Function Oxygenases, Multienzyme Complexes, Nerve Growth Factors, Neuropeptides, Neurotransmitter Agents, Oligonucleotide Array Sequence Analysis, Organ Culture Techniques, Pituitary Adenylate Cyclase-Activating Polypeptide, Rats, Rats, Sprague-Dawley, Tyrosine 3-Monooxygenase, Up-Regulation

Lithium inhibits inositol monophosphatase at therapeutically effective concentrations, and it has been hypothesized that depletion of brain inositol levels is an important chemical alteration for lithium's therapeutic efficacy in bipolar disorder. We have employed adult rat cortical slices as a model to investigate the gene regulatory consequences of inositol depletion effected by lithium using cytidine diphosphoryl-diacylglycerol as a functionally relevant biochemical marker to define treatment conditions. Genes coding for the neuropeptide hormone pituitary adenylate cyclase activating polypeptide (PACAP) and the enzyme that processes PACAP's precursor to the mature form, peptidylglycine alpha-amidating monooxygenase, were upregulated by inositol depletion. Previous work has shown that PACAP can increase tyrosine hydroxylase (TH) activity and dopamine release, and we found that the gene for GTP cyclohydrolase, which effectively regulates TH through synthesis of tetrahydrobiopterin, was also upregulated by inositol depletion. We propose that modulation of brain PACAP signaling might represent a new opportunity in the treatment of bipolar disorder.


Alternate JournalNeuron
PubMed ID15797548