Decreased Glutamic Acid Decarboxylase67 Messenger RNA Expression in a Subset of Prefrontal Cortical γ-Aminobutyric Acid Neurons in Subjects With Schizophrenia

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

doi:10.1001/archpsyc.57.3.237

Cited by 613 publications

(512 citation statements)

References 56 publications

(48 reference statements)

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“…In the prefrontal cortex of schizophrenics, a reduction in the number of cells expressing GAD 67 mRNA has been reported by two different groups (Akbarian et al 1995;Volk et al 2000).…”

Section: Postmortem Evidence For a Gaba Defect In Schizophreniamentioning

confidence: 84%

GABAergic Interneurons Implications for Understanding Schizophrenia and Bipolar Disorder

Beneš

Berretta

2001

Neuropsychopharmacology

989

643

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Neurons that express the compound, ␥ -aminobutyric acid (GABA), are broadly present throughout the central nervous system, although telencephalic structures, such as the cerebral cortex, show the most abundant quantities of this neurotransmitter (Jones 1987). In the discussion that follows, the anatomy and physiology of various types of GABAergic interneurons in the cortex and hippocampus will be discussed and related to recent postmortem studies implicating this transmitter system in the pathophysiology of schizophrenia and bi- 25 , NO . 1 polar disorder and their treatment with neuroleptic drugs (for more comprehensive reviews on cortical and hippocampal neurons see: Hof et al. 1993;Freund and Buzsaki 1996;Somogyi et al. 1998). NEUROBIOLOGY OF GABAERGIC INTERNEURONSBased on Golgi-impregnation studies, Ramon y Cajal provided the first descriptions of several different morphological subtypes of interneurons in the cerebral cortex and hippocampus (Ramon y Cajal 1893, 1911. In more recent years, it has been shown that, with some overlap, different morphological subtypes also have distinct distributions, connectivity, neurochemistry, and electrophysiological properties (for reviews see Hof et al. 1993;Freund and Buzsaki 1996). It is interesting to note that every segment of a pyramidal neuron, such as the soma, dendritic branches and spines, and the initial axonal segment, receives dense GABAergic synaptic innervation (O'Kusky and Colonnier 1982;Hendry et al. 1983;Houser et al. 1983; Beaulieu et al. 1992; for reviews see Jones 1993;Freund and Buzsaki 1996). Even more interestingly, each of these segments appears to be innervated by distinct GABAergic neuronal subtypes (see below).These differences strongly suggest that each of these subtypes plays a fundamentally different role in physiological and pathological mechanisms. In the discussion that follows, cortical interneurons will be described first, since our most basic understanding of GABAergic cells is derived from these populations. In more recent years, however, similar characterizations of interneurons in hippocampus have emerged. Although these cells show some striking similarities to their cortical counterparts, there are also some unique features that distinguish them. For this reason, interneurons in the hippocampus are discussed separately. Cortex Neuroanatomical Studies of Cortical Interneurons.Various types of GABAergic neurons can be categorized according to the type of synaptic profiles they are associated with, as this has direct implications for understanding the physiological role of these cells in cortical circuits. These categories are discussed below.A XO -S OMATIC I NHIBITORY S YNAPSES (B ASKET C ELLS ). The most commonly encountered interneurons ( Figure 1A) are multipolar in shape, i.e., they may have three or more primary dendritic branches emanating from their cell bodies, some having somata that are as large as those of pyramidal neurons (Jones and Hendry 1984). Using immunocytochemistry to localize the enzyme ). These cells also ...

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“…In the prefrontal cortex of schizophrenics, a reduction in the number of cells expressing GAD 67 mRNA has been reported by two different groups (Akbarian et al 1995;Volk et al 2000).…”

Section: Postmortem Evidence For a Gaba Defect In Schizophreniamentioning

confidence: 84%

GABAergic Interneurons Implications for Understanding Schizophrenia and Bipolar Disorder

Beneš

Berretta

2001

Neuropsychopharmacology

989

643

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“…Our recent unpublished observations also reveal a reduction in the density of CB-IR interneurons in dlPFC of subjects with schizophrenia (Rajkowska et al, 2002). Moreover, reductions in immunoreactivity for glutamic acid decarboxylase (GAD65) (the GABA synthesizing enzyme; Benes et al, 2000), mRNA for GAD (Akbarian et al, 1995;Hashimoto and Lewis, 2006;Hashimoto et al, 2003;Volk et al, 2000), and the GABA membrane transporter, GAT-1 (Pierri et al, 1999;Woo et al, 1998) have been observed in dlPFC and anterior cingulate cortex in manic-depressive disorder and schizophrenia. Whether similar reductions in GAD or GAT-1 mRNA and protein are present in our cohort of depressed subjects is yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

GABAergic Neurons Immunoreactive for Calcium Binding Proteins are Reduced in the Prefrontal Cortex in Major Depression

Rajkowska

O'Dwyer

Teleki

et al. 2006

Neuropsychopharmacol

366

234

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Post-mortem morphometric studies report reductions in the average density and size of cortical neurons in the dorsolateral prefrontal cortex (dlPFC) and orbitofrontal cortex (ORB) in major depressive disorder (MDD). The contribution of specific neuronal phenotypes to this general pathology in depression is still unclear. Post-mortem sections from the dlPFC and ORB regions of 14 subjects with MDD and 11 controls were immunostained to visualize calbindin-immunoreactive (CB-IR) and parvalbumin-immunoreactive (PV-IR) presumptive GABAergic neurons. A three-dimensional cell counting probe was used to assess the cell packing density and size of CB-IR neurons in layers II + IIIa and PV-IR neurons in layers III-VI. The density of CB-IR neurons was significantly reduced by 50% in depression in the dlPFC and there was a trend toward reduction in the ORB. The size of CB-IR somata was significantly decreased (18%) in depression in the dlPFC with a trend toward reduction in the ORB. In contrast, there was no difference in the density of PV-IR neurons between the depressed and control groups in the dlPFC. The size of PV-IR neuronal soma was unchanged in depressed compared to control subjects in either dlPFC or ORB. In depression, subpopulations of GABAergic neurons may be affected differently in dlPFC and ORB. A significant reduction in the density and size of GABAergic interneurons immunoreactive for calcium binding proteins was found predominantly in the dlPFC region. These cellular changes are consistent with recent neuroimaging studies revealing a reduction in the cortical levels of GABA in depression.

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“…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%

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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Decreased Glutamic Acid Decarboxylase67 Messenger RNA Expression in a Subset of Prefrontal Cortical γ-Aminobutyric Acid Neurons in Subjects With Schizophrenia

Cited by 613 publications

References 56 publications

GABAergic Interneurons Implications for Understanding Schizophrenia and Bipolar Disorder

GABAergic Interneurons Implications for Understanding Schizophrenia and Bipolar Disorder

GABAergic Neurons Immunoreactive for Calcium Binding Proteins are Reduced in the Prefrontal Cortex in Major Depression

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

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