Cerebrospinal fluid metabolomics identifies a key role of isocitrate dehydrogenase in bipolar disorder: evidence in support of mitochondrial dysfunction hypothesis.

Although evidence for mitochondrial dysfunction in the pathogenesis of bipolar disorder (BD) has been reported, the precise biological basis remains unknown, hampering the search for novel biomarkers. In this study, we performed metabolomics of cerebrospinal fluid (CSF) from male BD patients (n=54) and age-matched male healthy controls (n=40). Subsequently, post-mortem brain analyses, genetic analyses, metabolomics of CSF samples from rats treated with lithium or valproic acid were also performed. After multivariate logistic regression, isocitric acid (isocitrate) levels were significantly higher in the CSF from BD patients than healthy controls. Furthermore, gene expression of two subtypes (IDH3A and IDH3B) of isocitrate dehydrogenase (IDH) in the dorsolateral prefrontal cortex from BD patients was significantly lower than that of controls, although the expression of other genes including, aconitase (ACO1, ACO2), IDH1, IDH2 and IDH3G, were not altered. Moreover, protein expression of IDH3A in the cerebellum from BD patients was higher than that of controls. Genetic analyses showed that IDH genes (IDH1, IDH2, IDH3A, IDH3B) and ACO genes (ACO1, ACO2) were not associated with BD. Chronic (4 weeks) treatment with lithium or valproic acid in rats did not alter CSF levels of isocitrate, and mRNA levels of Idh3a, Idh3b, Aco1 and Aco2 genes in the rat brain. These findings suggest that abnormality in the metabolism of isocitrate by IDH3A in the mitochondria plays a key role in the pathogenesis of BD, supporting the mitochondrial dysfunction hypothesis of BD. Therefore, IDH3 in the citric acid cycle could potentially be a novel therapeutic target for BD.

Glutamate Signaling in Synaptogenesis and NMDA Receptors as Potential Therapeutic Targets for Psychiatric Disorders.

Glutamate, a major excitatory neurotransmitter, plays important roles in synaptic plasticity, such as long-term potentiation (LTP) and new synapse formation. Growing evidence suggests that glutamate signaling is involved in the neurobiology of psychiatric disorders, including schizophrenia, major depressive disorder (MDD) and bipolar disorder (BP). Postmortem brain studies demonstrated altered spine density in brains from patients with these psychiatric disorders, indicating that remodeled neuronal circuits may contribute to the pathobiology of these psychiatric diseases. Drugs targeting the glutamate system have typically attracted attention as they show efficacy in animal studies and potential therapeutic effects in the clinical setting. In particular, the Nmethyl- D-aspartate (NMDA) receptor antagonist, ketamine exerts a rapid and robust antidepressant effect in treatment-resistant patients with MDD and BP, whereas conventional antidepressants require several weeks for therapeutic onset. Animal studies showed that ketamine induced rapid synaptogenesis, suggestive of synaptic plasticity via NMDA receptor signaling being an essential event in the treatment of depression. Therefore, drugs modulating glutamate signaling could also be potential therapeutic drugs for psychiatric disorders. First, we summarize the role of glutamate signaling on dendritic spine formation, maintenance and remodeling. Then, we discuss the abnormalities identified in dendritic spine and glutamate signaling from postmortem brain studies and animal models of psychiatric disorders. Finally, we review the potential benefits of drugs acting on the NMDA receptor in clinical and animal models of psychiatric disorders.

Synthesis of nano-TaO(x) oxygen reduction reaction catalysts on multi-walled carbon nanotubes connected via a decomposition of oxy-tantalum phthalocyanine.

Nano-TaOx particles were supported on multi-walled carbon nanotubes via the thermal decomposition of oxy-tantalum phthalocyanine. The phthalocyanine-derived carbon connected TaOx particles with the nanotube-support to provide a conductive path. The oxygen reduction reaction activity, which solely originated from TaOx, was above 0.9 V with larger currents than conventional TaOx particles in acidic media.