Lithium (Li) is commonly used in the treatment of bipolar disorder (BPD). However, the molecular mechanism of its action has not completely understood. MicroRNAs (miRNAs), a class of small RNA species are recognized as important regulators in post-transcription gene expression. To explore the role of miRNA in Li action, we quantitatively analyzed the expression patterns of 13 miRNAs in 20 lymphoblastoid cell lines (LCLs) with or without Li treatment in culture. Using paired t statistics in the analysis, we identified significant changes in seven of the 13 miRNAs tested in LCLs sampled at treatment day 4 (P < 0.05). Four of the seven significant miRNAs, miR-34a, miR-152, miR-155, and miR-221 consistently changed expression in the same LCLs at a longer treatment time point day 16 (Bonferroni P < 0.05). Interestingly, miR-221 and miR-34a also changed expression in rat hippocampus in response to Li treatment (Zhou et al., 2008), though in the opposite direction. We focused on the predicted target mRNAs of miR-221 and miR-34a, and identified 29 and ten targets that were strongly and inversely correlated in expression with the two miRNAs, respectively. At present we tested a subset of miRNAs, our results suggest that miRNAs are excellent candidates for the study of the molecular basis of Li’s treatment action in cell systems such as lymphocytes given limited access to the human brain.

MicroRNAs (miRNA) are endogenous tissue-specific short RNAs that regulate gene expression. Discriminating each let-7 family member expression is especially important due to let-7's abundance and connection with development and cancer. However, short lengths (22 nt) and similarities between multiple sequences have prevented identification of individual members. Here, we present ProDeG, a computational algorithm which designs imperfectly matched sequences (previously yielding only noise levels in microarray experiments) for genome-wide microarray “signal” probes to discriminate single nucleotide differences and to improve probe qualities. Our probes for the entire let-7 family are both homogeneous and specific, verified using microarray signals from fluorescent dye-tagged oligonucleotides corresponding to the let-7 family, demonstrating the power of our algorithm. In addition, false let-7c signals from conventional perfectly-matched probes were identified in lymphoblastoid cell-line samples through comparison with our probe-set signals, raising concerns about false let-7 family signals in conventional microarray platform.

Objectives Bipolar disorder (BD) is a mental illness of unknown neuropathology and has several genetic associations. Antipsychotics are effective for the treatment of acute mania, psychosis, or mixed states in BD individuals. We aimed to identify gene transcripts differentially expressed in postmortem brains from BD individuals in both the antipsychotics-exposed (exposed) and non-exposed groups and controls. Methods We quantified the abundance of gene transcripts in postmortem brains (brains) of seven exposed, seven non-exposed, and 12 controls with the Affymetrix U133P2 GeneChip microarrays and technologies. We applied a q-value of ≤ 0.005 to identify statistically significant transcripts with mean abundance differences between non-exposed and controls (and/or exposed). Results We identified 2,191 unique genes with significantly altered expression levels in non-exposed brains compared to those in the control and exposed groups. The expression levels of these genes were not significantly different between exposed and controls, suggesting a normalization effect of antipsychotics on the expression of these genes. Gene Ontology (GO) enrichment analysis showed significant (Bonferroni p ≤ 0.05) clustering of subgroups of the 2,191 genes under a broad number of GO terms, noticeably the protein products of genes enriched are critical to the function of synapses, including intracellular protein trafficking, synaptic vesicle biogenesis, transport, releasing and recycling, as well as organization and stabilization of the node of Ranvier. Conclusions These results support a hypothesis of synaptic and intercellular communication impairment in BD. The apparent normalization of expression patterns with exposure to antipsychotic medication may represent a physiological process that relates both to etiology and improvement patterns of the disorder.

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