Disruption of Glutamate-Glutamine-GABA Cycle Significantly Impacts on Suicidal Behaviour: Survey of the Literature and Own Findings on Glutamine Synthetase.

Department of Psychiatry, University of Magdeburg, Leipziger Str.44, D-39120Magdeburg, Germany. .
CNS & neurological disorders drug targets (Impact Factor: 2.63). 08/2013; 12(7). DOI: 10.2174/18715273113129990091
Source: PubMed


The aetiology of suicide is complex and still not completely understood. The present communication, which consists of two parts, aims to shed some light on the role of amino acidergic neurotransmission in suicide. In the first part we provide an overview of the literature showing that with the exception of certain gamma-aminobutyric acid transporters, virtually all components of the glutamate-glutamine- gamma-aminobutyric acid cycle are, in some way or other, abnormal in suicide victims, which indicates a prominent involvement of the glutamatergic and gamma-aminobutyric acidergic neurotransmitter systems in suicidal behaviour. In the second part we present own immunohistochemical findings showing that densities of glutamine synthetase expressing glial cells in the mediodorsal thalamus as well as in the dorsolateral prefrontal and orbitofrontal cortex of schizophrenic suicide completers are significantly elevated compared with controls and non-suicide individuals with schizophrenia, thus calling into question the belief that cerebral glutamine synthetase deficit is indicative of suicidal behaviour.

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    • "Subsequently , ammonium nickel sulfate hexahydrate was added to enhance the immunoreaction ( Bernstein et al . , 2013 ) . For control purposes , the primary antiserum was replaced by either buffer or normal serum . Further control experiments involved the application of the GS antiserum after preabsorption with GS protein ( recombinant human GS , charge number CE02 ; from Novoprotein , Shanghai , China ) as described earlier in detail ( Bernstein et al"
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    ABSTRACT: There is increasing evidence for disturbances within the glutamate system in patients with affective disorders, which involve disruptions of the glutamate-glutamine-cycle. The mainly astroglia-located enzyme glutamine synthetase (GS) catalyzes the ATP-dependent condensation of ammonia and glutamate to form glutamine, thus playing a central role in glutamate and glutamine homoeostasis. However, GS is also expressed in numerous oligodendrocytes (OLs), another class of glial cells implicated in mood disorder pathology. To learn more about the role of glia-associated GS in mental illnesses, we decided to find out if numerical densities of glial cells immunostained for the enzyme protein differ between subjects with major depressive disorder, bipolar disorder (BD), and psychically healthy control cases. Counting of GS expressing astrocytes (ACs) and OLs in eight cortical and two subcortical brain regions of subjects with mood disorder (N = 14), BD (N = 15), and controls (N = 16) revealed that in major depression the densities of ACs were significantly reduced in some cortical but not subcortical gray matter areas, whereas no changes were found for OLs. In BD no alterations of GS-immunoreactive glia were found. From our findings we conclude that (1) GS expressing ACs are prominently involved in glutamate-related disturbances in major depression, but not in BD and (2) GS expressing OLs, though being present in significant numbers in prefrontal cortical areas, play a minor (if any) role in mood disorder pathology. The latter assumption is supported by findings of others showing that - at least in the mouse brain cortex - GS immunoreactive oligodendroglial cells are unable to contribute to the glutamate-glutamine-cycle due to the complete lack of amino acid transporters (Takasaki et al., 2010).
    Frontiers in Cellular Neuroscience 08/2015; 9:273. DOI:10.3389/fncel.2015.00273 · 4.29 Impact Factor
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    • "Multiple subcellular compartments of glutamate are located within both neurons and astrocytes , and glutamate can be derived from other amino acids and many energy substrates, including glucose, lactate and 3-hydroxybutyrate (McKenna, 2007). A disruption of glutamate–glutamine cycle significantly impacts on suicidal behavior (Bernstein et al., 2013). "
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    ABSTRACT: Major depression is a common, recurrent mental illness that affects millions of people worldwide. Recently, a unique fast neuroprotective and antidepressant treatment effect has been observed by ketamine, which acts via the glutamatergic system. Hence, a steady accumulation of evidence supporting a role for the excitatory amino acid neurotransmitter (EAA) glutamate in the treatment of depression has been observed in the last years. Emerging evidence indicates that N-methyl-D-aspartate (NMDA), group 1 metabotropic glutamate receptor antagonists and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) agonists have antidepressant properties. Indeed, treatment with NMDA receptor antagonists has shown the ability to sprout new synaptic connections and reverse stress-induced neuronal changes. Based on glutamatergic signaling, a number of therapeutic drugs might gain interest in the future. Several compounds such as ketamine, memantine, amantadine, tianeptine, pioglitazone, riluzole, lamotrigine, AZD6765, magnesium, zinc, guanosine, adenosine aniracetam, traxoprodil (CP-101,606), MK-0657, GLYX-13, NRX-1047, Ro25-6981, LY392098, LY341495, D-cycloserine, D-serine, dextromethorphan, sarcosine, scopolamine, pomaglumetad methionil, LY2140023, LY404039, MGS0039, MPEP, 1-Aminocyclopropanecarboxylic acid all of which target this system have already been brought up, some of them recently. Drugs targeting the glutamatergic system might open up a promising new territory for the development of drugs to meet the needs of patients with major depression. Copyright © 2015. Published by Elsevier Inc.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 03/2015; 64. DOI:10.1016/j.pnpbp.2015.02.015 · 3.69 Impact Factor
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    • "Additionally, the glutamate transporter for astrocytes, GLT-1, is increased in schizophrenia patients (162). Although Arai et al. (163) reported no association between glutamine synthetase and schizophrenia, the enzyme glutamine synthetase displays gender-specific differences in schizophrenia (164) and is involved in suicidal behavior (165, 166). Moreover, the atypical antipsychotic agent risperidone increases glutamine synthetase levels (167). "
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    ABSTRACT: Dopamine is an inhibitory neurotransmitter involved in the pathology of schizophrenia.The revised dopamine hypothesis states that dopamine abnormalities in the mesolimbic and prefrontal brain regions exist in schizophrenia. However, recent research has indicated that glutamate, GABA, acetylcholine, and serotonin alterations are also involved in the pathology of schizophrenia. This review provides an in-depth analysis of dopamine in animal models of schizophrenia and also focuses on dopamine and cognition. Furthermore, this review provides not only an overview of dopamine receptors and the antipsychotic effects of treatments targeting them but also an outline of dopamine and its interaction with other neurochemical models of schizophrenia. The roles of dopamine in the evolution of the human brain and human mental abilities, which are affected in schizophrenia patients, are also discussed.
    Frontiers in Psychiatry 05/2014; 5. DOI:10.3389/fpsyt.2014.00047
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