Bipolar affective disorder is a severe and debilitating psychiatric condition characterized by the alternating mood states of mania and depression. Both the molecular pathophysiology of the disorder and the mechanism of action of the mainstays of its treatment remain largely unknown. Here, 1 H NMR spectroscopy-based metabonomic analysis was performed to identify molecular changes in post-mortem brain tissue (dorsolateral prefrontal cortex) of patients with a history of bipolar disorder. The observed changes were then compared to metabolic alterations identified in rat brain following chronic oral treatment with either lithium or valproate. This is the first study to use 1 H NMR spectroscopy to study post-mortem bipolar human brain tissue, and it is the first to compare changes in disease brain with changes induced in rat brain following mood stabilizer treatment. Several metabolites were found to be concordantly altered in both the animal and human tissues. Glutamate levels were increased in post-mortem bipolar brain, while the glutamate/glutamine ratio was decreased following valproate treatment, and c-aminobutyric acid levels were increased after lithium treatment, suggesting that the balance of excitatory/inhibitory neurotransmission is central to the disorder. Both creatine and myo-inositol were increased in the post-mortem brain but depleted with the medications. Lastly, the level of N-acetyl aspartate, a clinically important metabolic marker of neuronal viability, was found to be unchanged following chronic mood stabilizer treatment. These findings promise to provide new insight into the pathophysiology of bipolar disorder and may be used to direct research into novel therapeutic strategies.

Protein phosphatase inhibitor-1 is a prototypical mediator of cross-talk between protein kinases and protein phosphatases. Activation of cAMP-dependent protein kinase results in phosphorylation of inhibitor-1 at Thr-35, converting it into a potent inhibitor of protein phosphatase-1. Here we report that inhibitor-1 is phosphorylated in vitro at Ser-67 by the proline-directed kinases, Cdk1, Cdk5, and mitogen-activated protein kinase. By using phosphorylation state-specific antibodies and selective protein kinase inhibitors, Cdk5 was found to be the only kinase that phosphorylates inhibitor-1 at Ser-67 in intact striatal brain tissue. In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. The state of phosphorylation of inhibitor-1 at Ser-67 was dynamically regulated in striatal tissue by glutamatedependent regulation of N-methyl-D-aspartic acid-type channels. Phosphorylation of Ser-67 did not convert inhibitor-1 into an inhibitor of protein phosphatase-1. However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation.Control of protein phosphorylation/dephosphorylation occurs through regulation of protein kinase and protein phosphatase activities and is an integral component of intracellular signal transduction. Inhibitor-1 was the first endogenous molecule found to regulate protein phosphatase activity (1). Inhibitor-1 purified from rabbit skeletal muscle is an 18,700-kDa acid-and heat-stable protein composed of 166 amino acids that are highly conserved throughout phylogeny (2, 3). When phosphorylated at Thr-35 by cAMP-dependent protein kinase (PKA), 1 inhibitor-1 selectively and potently inhibits type 1 protein phosphatase (protein phosphatase-1, PP-1) with an IC 50 value of ϳ1 nM (4 -7). Phospho-Thr-35 inhibitor-1 is dephosphorylated by Ca 2ϩ /calmodulin-dependent protein phosphatase 2B (PP-2B, calcineurin) and protein phosphatase 2A (PP-2A), with PP-2B activity predominating in the presence of Ca 2ϩ (8 -11). First messengers such as neurotransmitters (e.g. dopamine and acetylcholine) and hormones (e.g. adrenaline) that elevate intracellular cAMP levels promote PKA-dependent phosphorylation of inhibitor-1 at Thr-35 in various tissues. PP-1 inhibition by phospho-Thr-35 inhibitor-1 provides substantial amplification of PKA-dependent signaling cascades and modulates the intensity and duration of a number of physiological responses including regulatory aspects of the cell cycle, gene expression, carbohydrate and lipid metabolism, and synaptic plasticity (12-17).Inhibitor-1 is widely expressed in mammalian tissue with highest levels occurring in the brain, skeletal muscle, adipose, and kidney tissues (18 -26). Within the brain, the highest levels of inhibitor-1 i...

BackgroundPrevious studies of brain and peripheral tissues in schizophrenia patients have indicated impaired energy supply to the brain. A number of studies have also demonstrated dysfunction of the microvasculature in schizophrenia patients. Together these findings are consistent with a hypothesis of blood-brain barrier dysfunction in schizophrenia. In this study, we have investigated the cerebral vascular endothelium of schizophrenia patients at the level of transcriptomics.Methodology/Principal FindingsWe used laser capture microdissection to isolate both microvascular endothelial cells and neurons from post mortem brain tissue from schizophrenia patients and healthy controls. RNA was isolated from these cell populations, amplified, and analysed using two independent microarray platforms, Affymetrix HG133plus2.0 GeneChips and CodeLink Whole Human Genome arrays. In the first instance, we used the dataset to compare the neuronal and endothelial data, in order to demonstrate that the predicted differences between cell types could be detected using this methodology. We then compared neuronal and endothelial data separately between schizophrenic subjects and controls. Analysis of the endothelial samples showed differences in gene expression between schizophrenics and controls which were reproducible in a second microarray platform. Functional profiling revealed that these changes were primarily found in genes relating to inflammatory processes.Conclusions/SignificanceThis study provides preliminary evidence of molecular alterations of the cerebral microvasculature in schizophrenia patients, suggestive of a hypo-inflammatory state in this tissue type. Further investigation of the blood-brain barrier in schizophrenia is warranted.

Background Repetitive transcranial magnetic stimulation (TMS) is an FDA-approved antidepressant treatment but little is known of its mechanism of action. Specifically, downstream effects of TMS remain to be elucidated. Objective/Hypothesis To identify brain structural changes from TMS treatment of a treatment resistant depressive episode through an exploratory analysis Methods 27 subjects in a DSM-IV current major depressive episode and on a stable medication regimen, had a 3T magnetic resonance T1 structural scan before and after five weeks of standard TMS treatment to the left dorsolateral prefrontal cortex. 27 healthy volunteer (HVs) subjects had the same brain MRI acquisition. Voxel-based morphometry was performed using high dimensional non-linear diffusomorphic anatomical registration (DARTEL). Results Six clusters of grey matter volume (GMV) that were lower in pre-treatment MRI’s of depressed subjects than in HV’s. GMV in four of these regions increased in MDD after TMS treatment by 3.5% to 11.2%. The four brain regions that changed with treatment were centered in the left anterior cingulate cortex, the left insula, the left superior temporal gyrus and the right angular gyrus. Increases in the anterior cingulate GMV with TMS correlated with improvement in depression severity. Conclusions To our knowledge, this is the first study of brain structural changes during TMS treatment of depression. The affected brain areas are involved in cognitive appraisal, decision-making and subjective experience of emotion. These effects may have potential relevance for the antidepressant action of TMS.