GABA Transporter-1 mRNA in the Prefrontal Cortex in Schizophrenia: Decreased Expression in a Subset of Neurons

Volk, David W.; Austin, Mark C.; Pierri, Joseph N.; Sampson, Allan R.; Lewis, David A.

doi:10.1176/appi.ajp.158.2.256

Cited by 206 publications

(169 citation statements)

References 30 publications

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“…The amount of GABA and [1,2-13 C]GABA from [1,2-13 C]acetate remained unchanged, whereas, [2-13 C]GABA was decreased in the CRFC in the present study. Thus, GABA turnover from [1-13 C]glucose was affected, which corroborates recent reports of impaired activity of glutamic acid decarboxylase (GAD) in schizophrenic patients (Guidotti et al, 2000;Volk et al, 2000;Dracheva et al, 2004). In this context, it is noteworthy that a decrease in GAD 67 has been suggested as a link between the glutamatergic and dopaminergic theories of psychosis (Hossein Fatemi et al, 2005).…”

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

confidence: 88%

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

confidence: 88%

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

Kondziella

Brenner

Eyjolfsson

et al. 2005

Neuropsychopharmacol

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“…9,12 Second, long-term exposure of monkeys to typical (haloperidol) or atypical (olanzapine) antipsychotics did not alter mRNA levels for GAD 67 , SST or GABA A a1 subunit in the DLPFC (Figure 6). Third, the three subjects with schizophrenia (pairs 2, 9, 13), who were not receiving antipsychotics at the time of death, showed decreased expression for GABA-related transcripts in both microarray and qPCR studies (Figures 2 and 3).…”

Section: Discussionmentioning

confidence: 94%

“…Previous studies demonstrated mRNA expression deficits in PV-containing, but not in CR-containing, GABA neurons in the DLPFC of subjects with schizophrenia. 9,12,15 These changes were associated with the downregulation of GAT1 in the presynaptic terminals of PV-containing chandelier neurons 48 and the upregulation of GABA A receptor a2 subunit in the postsynaptic axon initial segments of pyramidal neurons (Figure 7, lower enlarged square). 21 Our current study suggests alterations in GABA neurotransmission provided by two additional subpopulations of DLPFC GABA neurons: SST-and NPYcontaining neurons and CCK-containing basket neurons, which predominately target the distal dendrites and cell bodies of pyramidal neurons, respectively.…”

Section: Discussionmentioning

confidence: 97%

“…28 Our observation of reduced levels of GAD 67 and GAT1 mRNAs in the DLPFC of the same subjects with schizophrenia and the correlation between these changes across pairs (r = 0.62, P < 0.018), although not significant after Bonferroni's correction, are consistent with previous studies indicating that both the synthesis and presynaptic reuptake of GABA are reduced in the subset of GABA neurons that express PV. 4,12,15,48 Because a primary reduction in GAT1 does not induce changes in the levels of GAD, 49 the downregulation of GAT1, which prolongs the activity of synaptically released GABA, 50 is likely to be a compensatory response to decreased GABA synthesis in these neurons. 4 The highly significant correlations among the gene expression changes for GAD 67 , SST and NPY suggest that GAD 67 mRNA expression is also decreased in another subset of GABA neurons that express both SST and NPY.…”

Section: Discussionmentioning

confidence: 99%

“…4 In nonhuman primates, normal working memory function depends on GABA-mediated circuitry in the DLPFC 5,6 and decreased levels of the mRNAs encoding the 67 kDa isoform of glutamic acid decarboxylase (GAD 67 ), an enzyme that synthesizes GABA, and GABA transporter 1 (GAT1), a presynaptic transporter for the reuptake of synaptically released GABA, have been replicated in multiple post-mortem studies of schizophrenia. [7][8][9][10][11][12][13] Indeed, an analysis of all post-mortem studies of schizophrenia conducted in specimens from the Stanley Neuropathology Consortium revealed that three genes expressed in GABA neurons (reelin, parvalbumin (PV) and GAD 67 ) had the most abnormal transcript and protein levels in schizophrenia. 14 At the cellular level, the density of neurons with detectable levels of GAD 67 mRNA was significantly decreased in schizophrenia subjects, 7,9 whereas in neurons with detectable levels of GAD 67 mRNA, the expression level per neuron did not differ from control values.…”

Section: Introductionmentioning

confidence: 99%

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Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia

et al. 2007

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In subjects with schizophrenia, impairments in working memory are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). This dysfunction appears to be due, at least in part, to abnormalities in c-aminobutyric acid (GABA)-mediated inhibitory circuitry. To test the hypothesis that altered GABA-mediated circuitry in the DLPFC of subjects with schizophrenia reflects expression changes of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission, we conducted a systematic expression analysis of GABA-related transcripts in the DLPFC of 14 pairs of schizophrenia and age-, sex-and post-mortem interval-matched control subjects using a customized DNA microarray with enhanced sensitivity and specificity. Subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding (1) presynaptic regulators of GABA neurotransmission (67 kDa isoform of glutamic acid decarboxylase (GAD 67 ) and GABA transporter 1), (2) neuropeptides (somatostatin (SST), neuropeptide Y (NPY) and cholecystokinin (CCK)) and (3) GABA A receptor subunits (a1, a4, b3, c2 and d). Real-time qPCR and/or in situ hybridization confirmed the deficits for six representative transcripts tested in the same pairs and in an extended cohort, respectively. In contrast, GAD 67 , SST and a1 subunit mRNA levels, as assessed by in situ hybridization, were not altered in the DLPFC of monkeys chronically exposed to antipsychotic medications. These findings suggest that schizophrenia is associated with alterations in inhibitory inputs from SST/NPY-containing and CCKcontaining subpopulations of GABA neurons and in the signaling via certain GABA A receptors that mediate synaptic (phasic) or extrasynaptic (tonic) inhibition. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia is mediated by altered GABA neurotransmission in certain DLPFC microcircuits.

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Cognitive Dysfunction in Schizophrenia

2006

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GABA Transporter-1 mRNA in the Prefrontal Cortex in Schizophrenia: Decreased Expression in a Subset of Neurons

Abstract: Both GABA synthesis and reuptake appear to be altered at the level of gene expression in a subset of GABA neurons, and the resulting changes in GABA neurotransmission may contribute to prefrontal cortex dysfunction in schizophrenia.

Cited by 206 publications

References 30 publications

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

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

Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia

Cognitive Dysfunction in Schizophrenia

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