Itzhak Levi

IMPA1 is Essential for Embryonic Development and Lithium-Like Pilocarpine Sensitivity

Lithium has been the standard pharmacological treatment for bipolar disorder over the last 50 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. We characterized the phenotype of mice with a dysfunctional IMPA1 gene (IMPA1−/−) to study the in vivo physiological functions of IMPA1, in general, and more specifically its potential role as a molecular target in mediating lithium-dependent physiological effects. Homozygote IMPA1−/− mice died in utero between days 9.5 and 10.5 post coitum (p.c.) demonstrating the importance of IMPA1 in early embryonic development. Intriguingly, the embryonic lethality could be reversed by myo-inositol supplementation via the pregnant mothers. In brains of adult IMPA1−/− mice, IMPase activity levels were found to be reduced (up to 65% in hippocampus); however, inositol levels were not found to be altered. Behavioral analysis of the IMPA1−/− mice indicated an increased motor activity in both the open-field test and the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures, the latter supporting the idea that IMPA1 represents a physiologically relevant target for lithium. In conclusion the IMPA1−/− mouse represents a novel model to study inositol homeostasis, and indicates that genetic inactivation of IMPA1 can mimic some actions of lithium.

Postmortem Parietal Cortex TPH2 Expression Is Not Altered in Schizophrenic, Unipolar-Depressed, and Bipolar Patients vs Control Subjects

Serotonin (5-hydroxytryptamine [5-HT]) is a neurotransmitter synthesized in the raphe nuclei of the brain stem in the central nervous system (CNS) and also in the periphery. Dysfunction of the serotonergic system has been implicated in the pathogenesis of psychiatric disorders. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT biosynthesis. For more than a decade, only one gene encoding TPH was identified in vertebrates. Recently, a second TPH gene, designated TPH2, was detected, located on human chromosome 12, a susceptibility region for affective disorders. TPH2 is predominantly expressed in the brain, whereas the classical TPH gene, TPH1, is expressed in peripheral tissues. The discovery of the brain-abundant TPH2 gene justifies a new concept of the CNS serotonergic system. TPH2, rather than TPH1, has now become a candidate gene for 5-HT-related affective disorders. We compared TPH2 mRNA levels in postmortem parietal cortex of unipolar-depressed, bipolar, and schizophrenic patients vs control subjects, using real-time reverse transcription polymerase chain reaction. No significant difference in TPH2 mRNA levels was found among the four diagnostic groups. The lack of difference might suggest that this gene is not involved in the etiology of of these psychiatric disorders. Alternatively, it is possible that the parietal cortex is not the relevant brain area involved in the pathophysiology of these disorders or that posttranscriptional modifications of TPH2 mRNA occur in these patients, causing changes in protein levels and/or enzymatic activity.

Inhibition of inositol monophosphatase (IMPase) at the calbindin-D28k binding site: molecular and behavioral aspects.

Bipolar-disorder (manic-depressive illness) is a severe chronic illness affecting ∼1% of the adult population. It is treated with mood-stabilizers, the prototypic one being lithium-salts (lithium), but it has life threatening side-effects and a significant number of patients fail to respond. The lithium-inhibitable enzyme inositol-monophosphatase (IMPase) is one of the viable targets for lithiums mechanism of action. Calbindin-D28k (calbindin) up-regulates IMPase activity. The IMPase-calbindincomplex was modeled using the program MolFit. The in-silico model indicated that the 55-66 amino-acid segment of IMPase anchors calbindin via Lys59 and Lys61 with a glutamate in between (Lys-Glu-Lys motif) and that the motif interacts with residues Asp24 and Asp26 of calbindin. We found that differently from wildtype calbindin, IMPase was not activated by mutated calbindin in which Asp24 and Asp26 were replaced by alanine. Calbindins effect was significantly reduced by a linear peptide with the sequence of amino acids 58-63 of IMPase (peptide 1) and by six amino-acid linear peptides including at least part of the Lys-Glu-Lys motif. The three amino-acid peptide Lys-Glu-Lys or five amino-acid linear peptides containing this motif were ineffective. Mice administered peptide 1 intracerebroventricularly exhibited a significant anti-depressant-like reduced immobility in the forced-swim test. Based on the sequence of peptide 1, and to potentially increase the peptides stability, cyclic and linear pre-cyclic analog peptides were synthesized. One cyclic peptide and one linear pre-cyclic analog peptide inhibited calbindin-activated brain IMPase activity in-vitro. Our findings may lead to the development of molecules capable of inhibiting IMPase activity at an alternative site than that of lithium.

Type 1 diabetes affects topoisomerase I activity and GlcNAcylation in rat organs: kidney liver and pancreas

Chronic hyperglycemia leads to the development of diabetes-induced organ complications, through changes in gene expression and protein function. We previously showed that in cell lines, topoisomerase I (topo I) is modified by O-GlcNAcylation, which affects its DNA relaxation activity. Since topo I participates in gene expression processes, we assumed that high glucose levels will affect its regulation and activity. Here we examined the effect of hyperglycemia on the regulation, GlcNAcylation and activity of topo I, in various internal rat organs that were subjected to diabetes-induced complications. Type 1 diabetes was induced in female rats by Streptozotocin injection. Topo I activity in nuclear protein extracts derived from diabetic and nondiabetic rat organs and topo I mRNA level were examined. Topo I and O-linked beta-N-acetylglucosamine (O-GlcNAc) transferase proteins and their O-GlcNAcylation were determined by western blot and immunoprecipitation assays. We show that topo I activity and enzyme protein level decreased in various tissues derived from the diabetic animals, whereas the enzyme mRNA level was not altered. Topo I protein was modified in vivo by O-GlcNAc, and O-GlcNAc transferase was coprecipitated with topo I protein, suggesting a possible interaction between both enzymes. This study demonstrates, for the first time, that topo I activity is regulated by high glucose levels, as a result of the diabetic state and is modified in vivo by O-GlcNAcylation, suggesting that topo I, an essential enzyme for gene expression, is involved in cellular processes which may lead to the pathogenesis of diabetic complications.

Robust adaptive nonlinear H ∞ control for robot manipulators

This paper provides a solution to the tracking problem of a robotic system in terms of a solution to a certain Linear Matrix Inequalities (LMIs), and in the presence of both exogenous disturbance and model uncertainties. Although this problem has been investigated extensively and numerous results are now available, the contribution of this paper is in its unique approach which consists of transforming the nonlinear underlying problem into a linear one, and thus achieving a simple and elegant solution by means of a linear Hinfin control theory.

Corrigendum to “Inhibition of inositol monophosphatase (IMPase) at the calbindin-D28k binding site: Molecular and behavioural aspects” [Eur. Neuropsychopharmacol. 23 (2013) 1806–1815]

Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel Psychiatry Research Unit, Mental Health Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel Department of Chemical Research Support, Weizmann Institute of Science, Rehovot, Israel Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel Institute of Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel

Nonlinear Adaptive H∞ Output Feedback Tracking Control for Robotic Systems

Abstract This paper presents a solution to the tracking control problem of robotic systems in the presence of exogenous disturbances and model uncertainty with partial state information. The solution yields a Linear Matrix Inequalities (LMIs) based tracking output feedback controller. The main contribution of this paper lies in its particular approach which facilitates an application of the linear H ∞ control theory without linearizing the underlying system. This yields a relatively simple and elegant design procedure. In addition, a relatively low gain controller is achieved. Simulation results of application this control algorithm in a two-degree of freedom robot demonstrates the design procedure feasibility.