Glutamine synthetase and glutamate dehydrogenase in the prefrontal cortex of patients with schizophrenia

Бурбаева, Г. Ш.; Boksha, Irina S.; Turishcheva, Marina S.; Vorobyeva, E. А.; Savushkina, Olga K.; Tereshkina, Elena B.

doi:10.1016/s0278-5846(03)00078-2

Cited by 81 publications

(61 citation statements)

References 20 publications

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“…Furthermore, glutamine synthetase expression changes have also been found in post mortem brain tissue. Our present results of decreased glutamine synthetase are consistent with those of Burbaeva et al, who reported deceased protein expression in area 10 of the PFC (Burbaeva et al, 2003). A proteomic study by Prabakaran et al also described reduced glutamine synthetase in schizophrenia in area 9 of the frontal cortex (Prabakaran et al, 2004).…”

Section: Expression Of Glutamine Synthetase In Schizophreniasupporting

confidence: 92%

“…In turn, this could cause astrocytes to decrease production of glutamine synthetase or to increase protein disassembly and degradation to correct for abnormally high activity (Kosenko et al, 2003). So far, studies have not shown changes to glutamine synthetase activity in the brain in schizophrenia (Burbaeva et al, 2003, Gluck et al, 2002.…”

Section: Expression Of Glutamine Synthetase In Schizophreniamentioning

confidence: 99%

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Cortical expression of glial fibrillary acidic protein and glutamine synthetase is decreased in schizophrenia

Steffek¹,

McCullumsmith²,

Haroutunian³

et al. 2008

Schizophrenia Research

110

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Altered expression of structural and functional molecules expressed by astrocytes may play a role in the pathophysiology of schizophrenia. We investigated the hypothesis that the astrocytic enzyme glutamine synthetase, involved in maintaining the glutamate-glutamine cycle, and the cytoskeletal molecule glial fibrillary acidic protein (GFAP) are abnormally expressed in schizophrenia. We used Western blot analysis to measure levels of glutamine synthetase and GFAP in several brain regions of subjects with schizophrenia and a comparison group. We found that glutamine synthetase protein expression was significantly decreased in the superior temporal gyrus, and both glutamine synthetase and GFAP were significantly reduced in the anterior cingulate cortex in schizophrenia. Neither molecule demonstrated altered expression in the dorsolateral prefrontal cortex, primary visual cortex, or hippocampus. Chronic treatment with haloperidol did not alter the expression of these molecules in the rat brain, suggesting that our findings are not due to a medication effect. These data support an astrocytic component to the pathophysiology of schizophrenia and suggest that astrocytic molecules involved in enzymatic activity and cytoskeletal integrity may have a role in disease-related abnormalities in this illness.

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Section: Expression Of Glutamine Synthetase In Schizophreniasupporting

confidence: 92%

Section: Expression Of Glutamine Synthetase In Schizophreniamentioning

confidence: 99%

Cortical expression of glial fibrillary acidic protein and glutamine synthetase is decreased in schizophrenia

Steffek¹,

McCullumsmith²,

Haroutunian³

et al. 2008

Schizophrenia Research

110

View full text Add to dashboard Cite

show abstract

“…However, the reason for the increase in TCA cycling of precursors for glutamate from [1-13 C]glucose is not clear, but implies that label stays longer in the neuronal TCA cycle before incorporation into glutamate. That the glutamate-glutamine cycle is disrupted in schizophrenia patients as well is supported by the finding that activity of glutamine synthetase is decreased in brains of schizophrenic patients analyzed post mortem (Burbaeva et al, 2003). In this context, it must be recalled, however, that treatment with neuroleptics might contribute to a disrupted glutamate-glutamine cycle.…”

Section: Effects Of Repeated Mk801 On Metabolism D Kondziella Et Almentioning

confidence: 96%

Glial–Neuronal Interactions are Impaired in the Schizophrenia Model of Repeated MK801 Exposure

Kondziella

Brenner

Eyjolfsson

et al. 2005

Neuropsychopharmacol

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Schizophrenia-mimicking compounds such as phencyclidine (PCP) and MK801 are antagonists at the N-methyl-D-aspartate (NMDA) receptor and produce the whole spectrum of positive, negative, and cognitive symptoms. This is one of the most important pillars of the hypoglutamatergic hypothesis of schizophrenia. Since the synthesis of glutamate and GABA in neurons is closely connected to astrocyte metabolism, the study of astrocytic function is essential in this context. Dizocilpine-maleate (MK801) (0.5 mg/kg) was injected into rats every day for 6 days. The last dose was given together with [1-13 C]glucose and [1,2-13 C]acetate. Extracts from frontal, retrosplenial, and cingulate cortices (CRFC) and temporal lobes were examined by 13 C nuclear magnetic resonance spectroscopy, high pressure liquid chromatography, and light microscopy. In CRFC, significant increases in the levels of glutamate, glutathione, and taurine were seen, whereas amounts and turnover of noradrenaline, dopamine, and serotonin were unchanged. Glutamate and glutamine, derived from [1,2-13 C]acetate and thus astrocytes, were significantly decreased in CRFC as compared to controls. Labeling from [1-13 C]glucose and thus mostly neuronal metabolism was affected in the same brain region with decreased labeling of glutamate and GABA. The present model mimics the increased glutamate/glutamine activity found in drug-naive patients with first episode schizophrenia. Moreover, the decreased labeling indicates the transition to lower glutamatergic function seen in chronic schizophrenia patients. The disturbance in astrocytic function and the glutamine-glutamate-GABA cycle are of significant importance and might add to the malfunction of the cortico-striato-thalamo-cortical loop caused by NDMA receptor blockade.

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“…Glutamine production is also perturbed in pathological conditions. For example, patients with schizophrenia or mesial temporal lobe epilepsy both exhibit decreased glutamine synthetase expression in astrocytes (Burbaeva et al, 2003;Eid et al, 2004).…”

Section: Presynaptic Gaba Is Regulated By Synaptic Activitymentioning

confidence: 99%

Dynamic Regulation of Synaptic GABA Release by the Glutamate-Glutamine Cycle in Hippocampal Area CA1

2006

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Vesicular GABA and intraterminal glutamate concentrations are in equilibrium, suggesting inhibitory efficacy may depend on glutamate availability. Two main intraterminal glutamate sources are uptake by neuronal glutamate transporters and glutamine synthesized through the astrocytic glutamate-glutamine cycle. We examined the involvement of the glutamate-glutamine cycle in modulating GABAergic synaptic efficacy. In the absence of neuronal activity, disruption of the glutamate-glutamine cycle by blockade of neuronal glutamine transport with ␣-(methylamino) isobutyric acid (MeAIB; 5 mM) or inhibition of glutamine synthesis in astrocytes with methionine sulfoximine (MSO; 1.5 mM) had no effect on miniature IPSCs recorded in hippocampal area CA1 pyramidal neurons. However, after a period of moderate synaptic activity, application of MeAIB, MSO, or dihydrokainate (250 M; an astrocytic glutamate transporter inhibitor) significantly reduced evoked IPSC (eIPSC) amplitudes. The MSO effect could be reversed by exogenous application of glutamine (5 mM), whereas glutamine could not rescue the eIPSC decreases induced by the neuronal glutamine transporter inhibitor MeAIB. The activity-dependent reduction in eIPSCs by glutamate-glutamine cycle blockers was accompanied by an enhanced blocking effect of the low-affinity GABA A receptor antagonist, TPMPA [1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid], consistent with diminished GABA release. We further corroborated this hypothesis by examining MeAIB effects on minimal stimulation-evoked quantal IPSCs (meIPSCs). We found that, in MeAIB-containing medium, moderate stimulation induced depression in potency of meIPSCs but no change in release probability, consistent with reduced vesicular GABA content. We conclude that the glutamate-glutamine cycle is a major contributor to synaptic GABA release under physiological conditions, which dynamically regulates inhibitory synaptic strength.

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Glutamine synthetase and glutamate dehydrogenase in the prefrontal cortex of patients with schizophrenia

Cited by 81 publications

References 20 publications

Cortical expression of glial fibrillary acidic protein and glutamine synthetase is decreased in schizophrenia

Cortical expression of glial fibrillary acidic protein and glutamine synthetase is decreased in schizophrenia

Glial–Neuronal Interactions are Impaired in the Schizophrenia Model of Repeated MK801 Exposure

Dynamic Regulation of Synaptic GABA Release by the Glutamate-Glutamine Cycle in Hippocampal Area CA1

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