Implications for Altered Glutamate and GABA Metabolism in the Dorsolateral Prefrontal Cortex of Aged Schizophrenic Patients

Gluck, Martin R.; Thomas, Rohan G.; Davis, Kenneth L.; Haroutunian, Vahram

doi:10.1176/appi.ajp.159.7.1165

Cited by 95 publications

(75 citation statements)

References 56 publications

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“…Taken together, unchanged enzyme activity and expression changes of glutamine synthetase and GSLP in opposite directions suggest that these enzymes may be differentially regulated in disease states by astrocytes. Furthermore, these data suggest that the study of glutamine synthetase may be confounded by the presence of multiple distinct isoforms and that past reports of unchanged glutamine synthetase activity may have been due to a summation of activity from multiple isoforms (Gluck et al, 2002).…”

Section: Expression Of Glutamine Synthetase In Schizophreniamentioning

confidence: 87%

“…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

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113

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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 Schizophreniamentioning

confidence: 87%

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

Self Cite

113

View full text Add to dashboard Cite

show abstract

“…Decreased neuropil and neuronal size, rather than neuronal loss have been observed in the hippocampus (Benes et al, 1991). Altered functioning of neurotransmitters might be taking place (Deakin & Simpson, 1997b;Gluck et al, 2002). As reviewed by Deakin and Simpson (1997a), there is an asymmetric loss of glutamate terminals in the temporal lobe and reduced GABA function secondary to a loss of glutamatergic input.…”

Section: Discussionmentioning

confidence: 99%

Frontal lobe volumes in schizophrenia: Effects of stage and duration of illness

Premkumar

Kumari

Corr

et al. 2006

Journal of Psychiatric Research

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While the changes in the volume of the temporal lobe and its sub-regions over the course of illness have been studied in patients with schizophrenia, few studies have examined changes in the frontal lobe between the first episode and the chronic stage. In this study, we focussed on the effect of illness stage and duration of illness on the volume of frontal lobe regions, though we examined several other regions to establish the specificity of any effects observed for this region. We compared the volumes of brain regions among 34 first-episode schizophrenia patients, 49 chronic schizophrenia patients, 18 healthy controls matched, on average, to the first-episode patients and 21 healthy controls matched, on average, to the chronic patients. Logarithmic regression analyses examined the relationships between the duration of illness and the brain regional volumes in the patient group. The results showed that chronic patients had smaller prefrontal cortical grey matter volumes, but larger premotor cortical volumes compared to first-episode patients and matched healthy controls; they also had smaller parieto-occipital grey matter volumes and larger putamen and lateral ventricles. There was a significant exponential relation between the duration of illness and the volumes of these regions. The exponential relation suggests that the prefrontal cortex, premotor cortex, parieto-occipital cortex and putamen are susceptible to change as the disorder persists. The larger volumes of the premotor cortices in the chronic relative to the first-episode patients may reflect a compensatory mechanism of the premotor cortex following loss of function of the prefrontal cortex.Alternately, the enlargement of the premotor cortex may be secondary to that of the putamen, since brain enlargement in schizophrenia has been typically reported in the basal ganglia as a result of antipsychotic medication.

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“…An antagonism at this location could, in turn, cause regional hypermetabolism from increased glutamate release (Gluck et al, 2002;Theberge et al, 2002;Bartha et al, 1997;Moghaddam et al, 1997;Moghaddam and Adams, 1998). The mechanism for this phenomenon may be attributed to disinhibition of inhibitory interneurons in the anterior thalamus, basal forebrain, or frontal cortex (Farber, 2003;Carter et al, 2004;Tomitaka et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Effects of Noncompetitive NMDA Receptor Blockade on Anterior Cingulate Cerebral Blood Flow in Volunteers with Schizophrenia

Holcomb

Lahti

Medoff

et al. 2005

Neuropsychopharmacol

101

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Schizophrenia may be related to dysfunctional glutamatergic activity, specifically hypofunction of the N-methyl-D-aspartate receptor (NMDAR). In addition, it has been proposed that NMDAR hypofunction may paradoxically cause an increase in glutamate release and hypermetabolism in corticolimbic regions. If a state of partial, chronic NMDAR blockade underlies schizophrenia, then schizophrenic volunteers (SV) may have greater glutamate release and associated elevations in regional cerebral blood flow (rCBF) than normal volunteers (NV), following drug-induced NMDAR antagonism. Therefore, we have given acute ketamine, a noncompetitive NMDAR antagonist, to NV (n ¼ 13) and medicated volunteers with schizophrenia (n ¼ 10) in conjunction with serial positron emission tomography blood flow studies. Drug administration caused marked rCBF elevations in frontal and cingulate regions in both groups. Contrasts between NV and SV ketamine groups showed that SV had greater relative blood flow increases in the anterior cingulate than NV. Maximum blood flow, and the area under the curve for blood flow in the anterior cingulate cortex, significantly correlated with changes in psychosis ratings in SV and NV (maximum rCBF only). These changes are consistent with a relatively hypoactive thalamic NMDAR and increased cortical glutamate neurotransmission at non-NMDARs in schizophrenia. We hypothesize that ketamine antagonizes an NMDAR-dependent inhibitory system that is partially compromised in subjects with schizophrenia. The ketamine-induced reduction of inhibition leads to a marked increase in glutamate release and hypermetabolism (elevated rCBF) in frontal and cingulate cortical regions. The loss of inhibition and increased glutamate release may cause the distorted thoughts and diminished cognitive abilities elicited by NMDAR blockade.

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Implications for Altered Glutamate and GABA Metabolism in the Dorsolateral Prefrontal Cortex of Aged Schizophrenic Patients

Cited by 95 publications

References 56 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

Frontal lobe volumes in schizophrenia: Effects of stage and duration of illness

Effects of Noncompetitive NMDA Receptor Blockade on Anterior Cingulate Cerebral Blood Flow in Volunteers with Schizophrenia

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