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Objective: Morphometric studies of postmortem brains from subjects with mood disorders have reported altered density of glial cells in the amygdala; however, the nuclear regions have not been examined individually. Methods: We assessed the size and density of both neuronal and glial cells in discrete amygdalar nuclei in postmortem sections from subjects with major depressive disorder, bipolar disorder (BD) and schizophrenia and from nonpsychiatric control subjects. Three adjacent Nissl-stained sections were examined from each individual. Results: We report significantly decreased neuron somal size in the lateral amygdalar nucleus (LAN) and the accessory basal parvocellular nucleus (ABPC) in subjects with BD, relative to control subjects. These changes in cellular morphology were most prominent in the LAN in sections obtained from the left hemisphere. Conclusions: These findings add to increasing evidence for neuropathological changes in the amygdala of subjects with BD and specifically implicate the LAN and ABPC in this disorder. [ABSTRACT FROM AUTHOR]

Objective: Many studies indicate a genetic predisposition to bipolar disorder (BD) and suggest that a number of abnormal genes are involved in its development. In this study, we used DNA microarray technology to analyze gene-expression profiles in the postmortem frontal cortex of subjects with BD. Methods: Microarray hybridization was performed using human 19K microarray with universal human reference RNA in each hybridization. The reference cDNA was labelled with Cy3 and experimental cDNA, with Cy5. Glass array slides were cohybridized with equal amounts of mixed reference and experimental cDNA. Selected gene targets were further verified using real-time polymerase chain reaction (PCR). Results: We found that 831 genes were differentially expressed in subjects with BD, including a number of genes in the mitochondrial electron transport chain (ETC), phosphatidylinositol-signalling system and glycolysis/gluconeogenesis. Eight genes coding for the components of the mitochondrial ETC were identified along with 15 others related to mitochondrial function. Downregulation of NADH-ubiquinone oxidoreductase 20-kd subunit (ETC complex I), cytochrome c oxidase polypeptide Vic (ETC complex IV) and ATP synthase lipid-binding protein (ETC complex V) were further verified by real-time PCR. We also found that the expression of the NADH-ubiquinone oxidoreductase 20-kd subunit was increased in subjects with BD who were receiving mood-stabilizing treatment with lithium at the time of death, when compared with subjects with BD who were not being treated with lithium. Conclusions: Because the mitochondrial ETC is a major source for the generation of reactive oxygen species, these findings suggest that oxidative damage may play an important role in the pathophysiology of BD and that neuroprotection against this damage may be involved in the effect of lithium treatment. [ABSTRACT FROM AUTHOR]

Lithium, a common drug for the treatment of bipolar disorder (BD), requires chronic administration to prevent recurrences of the illness. The necessity for long-term treatment suggests that changes in genes expression are involved in the mechanism of its action. We studied effects of lithium on gene expression in lymphoblasts from BD patients, all excellent responders to lithium prophylaxis. Gene expression was analyzed using cDNA arrays that included a total of 2400 cDNAs. We found that chronic lithium treatment at a therapeutically relevant concentration decreased the expression of seven genes in lymphoblasts from lithium responders. Five of these, candidate lithiumregulated genes, including alpha | B-adrenoceptor (α | B-AR), acetylcholine receptor protein alpha chain precursor (ACHR), cAMPdependent 3′,5′-cyclic phosphodiesterase 4D (PDE4D), substance-P receptor (SPR), and ras-related protein RAB7, were verified by Northem blotting analysis in lithium responders. None of these genes were regulated by lithium in healthy control subjects. When we compared the expression of these five genes between bipolar subjects and healthy control subjects at baseline, prior to lithium administration, we found that α | B-AR gene expression was higher in bipolar subjects than in healthy control subjects. Our findings indicate that α | B-AR may play an important role in the mechanism of action of lithium treatment. [ABSTRACT FROM AUTHOR]

Hypoxia tolerance and adaptive regulation are important for aquatic animals, especially for species with poor mobility, such as most bivalves. Previous studies have confirmed that the blood clam Scapharca broughtonii has strong hypoxia resistance. However, the molecular mechanism supporting its hypoxic tolerance is still largely limited. To further screen the genes and their potential regulation of hypoxia tolerance, the transcriptome changes of S. broughtonii after acute hypoxic stress were explored by RNA sequencing. In this study, the average value of Q30 is 92.89%, indicating that the quality of sequencing is relatively high. The Unigenes obtained were annotated using four databases, namely Interpo, KEGG, Swisspro and TrEMBL. The annotation rates in these four databases were 71.82%, 75.95%, 92.98%, and 79.26%, respectively. And also, there were 649 DEGs in group B (dissolved oxygen (DO) of 2.5 mg/L) compared with group D (DO of 7.5 mg/L), among which 252 were up-regulated, and 397 were down-regulated. There were 965 DEGs in group A (DO of 0.5 mg/L), 2.5 mg/L, and 7.5 mg/L, compared with group B, among which 530 were up-regulated, and 435 were down-regulated. Meanwhile, there were 2,040 DEGs in group A compared with group D, among which 901 were up-regulated, and 1,139 were down-regulated. The main metabolic-related pathways of KEGG enriched in this study included Insulin secretion, Insulin signaling pathway, MAPK signal transduction pathway, and PPAR signaling pathway. These pathways may be critical metabolic pathways to solve energy demand and rebuild energy balance in S. broughtonii under hypoxic conditions. This study preliminarily clarified the response of S. broughtonii to hypoxia stress on the molecular levels, providing a reference for the following study on the response laws of related genes and pathways under environmental stress of S. broughtonii. [ABSTRACT FROM AUTHOR]

Oligonucleotide microarray technology was used to analyze gene expression profiles after chronic treatment with the mood stabilizing drug valproate at a therapeutically relevant concentration in primary cultured rat cerebral cortical cells. We discovered that valproate regulates expression of 28 genes, including three isoenzymes (M1, A3 and A4) of glutathione S-transferase (GST), an important protective factor against oxidative stress. Because previous studies in our laboratory found that chronic valproate treatment protected cultured neurons against oxidative stress, further experiments on the regulation of GST were performed. Regulation of GST M1, GST A3 and GST A4 was verified using northern blotting hybridization. Chronic valproate treatment increased mRNA levels of M1 and A4, but decreased the A3 mRNA level dose-dependently, indicating further complexities in the regulation of GST by valproate. The level of GST M1 protein and GST activity were also increased by chronic valproate treatment. In addition, chronic treatment with lithium, another commonly prescribed mood stabilizer, also increased levels of GST M1 mRNA and protein. The present findings suggest that regulation of GST M1, and possibly GST A4, may mediate the anti-oxidative effects of valproate treatment, and regulation of GST may be involved in the mood stabilizing effect of valproate and lithium. [ABSTRACT FROM AUTHOR]

Objective: Brain-derived neurotrophic factor (BDNF) is a key factor in neuroplasticity and has been implicated in the affective disorders; studies have demonstrated elevated BDNF in patients taking lithium and other mood stabilizers. The objective of our study was to analyze BDNF in lithium-responsive patients with bipolar disorder (BD) to further understand the role of BDNF in the pathophysiology of BD. Methods: Using enzyme-linked immunosorbent assay, we measured transformed B lymphocytes for BDNF protein. Results: BDNF levels were 36% lower in lymphoblasts from patients with BD (n = 12), compared with matched control participants (n = 13), and 55% lower when compared with their unaffected relatives (n = 14). Lithium significantly decreased BDNF levels in patients with BD and healthy control participants, although BDNF levels remained lower (33%) in the BD group posttreatment. Conclusion: Decreased BDNF may constitute part of the pathophysiologic process of BD in a lithium-responsive subgroup of individuals with this disease. A compensatory mechanism protecting the genetically predisposed unaffected relatives from phenotypic expression of BD is suggested. [ABSTRACT FROM AUTHOR]

Exposure to low Ca2+ and/or Mg2+ is tolerated by cardiac myocytes, astrocytes, and neurons, but restoration to normal divalent cation levels paradoxically causes Ca2+ overload and cell death. This phenomenon has been called the ‘Ca2+ paradox’ of ischemia-reperfusion. The mechanism by which a decrease in extracellular Ca2+ and Mg2+ is ‘detected’ and triggers subsequent cell death is unknown. Transient periods of brain ischemia are characterized by substantial decreases in extracellular Ca2+ and Mg2+ that mimic the initial condition of the Ca2+ paradox. In CA1 hippocampal neurons, lowering extracellular divalents stimulates a nonselective cation current. We show that this current resembles TRPM7 currents in several ways. Both (i) respond to transient decreases in extracellular divalents with inward currents and cell excitation, (ii) demonstrate outward rectification that depends on the presence of extracellular divalents, (iii) are inhibited by physiological concentrations of intracellular Mg2+, (iv) are enhanced by intracellular phosphatidylinositol 4,5-bisphosphate (PIP2), and (v) can be inhibited by Gaq-linked G protein-coupled receptors linked to phospholipase C β-induced hydrolysis of PIP2. Furthermore, suppression of TRPM7 expression in hippocampal neurons strongly depressed the inward currents evoked by lowering extracellular divalents. Finally, we show that activation of TRPM7 channels by lowering divalents significantly contributes to cell death. Together, the results demonstrate that TRPM7 contributes to the mechanism by which hippocampal neurons ‘detect’ reductions in extracellular divalents and provide a means by which TRPM7 contributes to neuronal death during transient brain ischemia. [ABSTRACT FROM AUTHOR]