Gene Expression for Glutamic Acid Decarboxylase Is Reduced Without Loss of Neurons in Prefrontal Cortex of Schizophrenics

Akbarian, Schahram; Kim, James J.; Potkin, Steven G.; Hagman, Jennifer O.; Tafazzoli, Alireza; Bunney, William E.; Jones, Edward G.

doi:10.1001/archpsyc.1995.03950160008002

Cited by 940 publications

(613 citation statements)

References 49 publications

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“…Activation of both prefrontal cortical interneurons and pyramidal cells is consistent with the actions of atypical APDs such as clozapine (Deutch and Duman, 1996). This is particularly interesting because the number and/or function of GABA interneurons in the PFC may be compromised in schizophrenia (Hashimoto et al, 2003;Benes et al, 2000;Lewis et al, 1999;Akbarian et al, 1995). Our data suggest that NT agonists activate PFC interneurons and could thereby compensate for a prefrontal cortical GABAergic deficit in schizophrenia.…”

Section: Discussionsupporting

confidence: 70%

The Neurotensin Agonist PD149163 Increases Fos Expression in the Prefrontal Cortex of the Rat

Petrie

Bubser

Casey

et al. 2004

Neuropsychopharmacol

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Dopaminergic axons innervating the prefrontal cortex (PFC) target both pyramidal cells and GABAergic interneurons. Many of these dopamine (DA) axons in the rat coexpress the peptide neurotransmitter neurotensin. Previous electrophysiological data have suggested that neurotensin activates GABAergic interneurons in the PFC. Activation of D2-like DA receptors increases extracellular GABA levels in the PFC, as opposed to the striatum, where D2 receptor activation inhibits GABAergic neurons. Because activation of presynaptic D 2 release-modulating autoreceptors in the PFC suppresses DA release but increases release of the cotransmitter neurotensin, D2 agonists may enhance the activity of GABAergic interneurons via release of neurotensin. In order to determine if neurotensin can activate GABAergic interneurons, we treated rats with the peptide neurotensin agonist, PD149163, and examined Fos expression in PFC neurons. Systemic administration of PD149163 increased overall Fos expression in the PFC, but not in the dorsal striatum. PD149163 induced Fos in PFC interneurons, as defined by the presence of calcium-binding proteins, and in pyramidal cells. Pretreatment with the high-affinity neurotensin antagonist, SR48692, blocked neurotensin agonist-induced Fos expression. These data suggest that neurotensin activates interneurons in the PFC of the rat.

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Section: Discussionsupporting

confidence: 70%

The Neurotensin Agonist PD149163 Increases Fos Expression in the Prefrontal Cortex of the Rat

Petrie

Bubser

Casey

et al. 2004

Neuropsychopharmacol

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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

353

231

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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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“…A decrease in the size of specific populations of cortical GABAergic synapses (Woo et al 1998) and of glutamic acid decarboxylase expression (Akbarian et al 1995;Impagnatiello et al 1998) and an increase in the number of GABA A receptors in cortical regions (Benes et al 1992;Benes et al 1996), suggestive of a reduced GABAergic tone, have been observed in post-mortem brain specimens obtained from individuals with schizophrenia. Moreover, it has been shown that long-term treatment with neuroleptics increases GABA-immunoreactive terminals in rodent medial prefrontal cortex (Vincent et al 1994) and elicits a dose-related increase of glutamic acid decarboxylase expression in hippocampus of schizophrenic patients (Todtenkopf and Benes 1998).…”

Section: Discussionmentioning

confidence: 99%

Clozapine, but not Haloperidol, Increases Brain Concentrations of Neuroactive Steroids in the Rat

Barbaccia

Affricano

Purdy

et al. 2001

Neuropsychopharmacology

103

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The extrapyramidal side effects of typical antipsychotics, which are induced to a markedly reduced extent by clozapine, have been linked to a dysfunction of central ␥ -aminobutyric acid (GABA)-mediated neurotransmission. The effects of clozapine on the brain concentrations of 3 ␣ -hydroxy-5 ␣ AP) and 3 ␣ , THDOC)Clozapine, the prototype of atypical antipsychotic drugs, exhibits the clinical efficacy of classical antipsychotics but lacks or induces to a greatly reduced extent most of the motor side effects of these latter drugs. The molecular mechanisms that underlie the pharmacological profile of clozapine remain unclear. Emphasis has been placed on the purported "selective" action of clozapine on mesocortical and mesolimbic dopaminergic pathways thought to result from its higher affinity for D 4 dopamine receptors than for D 2 receptors (Seeman 1992), as well as on its mixed antagonistic/agonistic action at D 2 and D 1 receptors (Coward et al. 1989;Brunello et al., 1995;Gerlach et al. 1996) and its high affinity for different subtypes of serotonin receptors (Brunello et al. 1995). More recently, the ratios of the affinities of clozapine for D 2 and 5HT 1a , D 2 and 5HT 1b or 5HT 1d , and D 2 and ␣ 2 -adrenergic receptors have been suggested to play a role in the anticata-

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Gene Expression for Glutamic Acid Decarboxylase Is Reduced Without Loss of Neurons in Prefrontal Cortex of Schizophrenics

Cited by 940 publications

References 49 publications

The Neurotensin Agonist PD149163 Increases Fos Expression in the Prefrontal Cortex of the Rat

The Neurotensin Agonist PD149163 Increases Fos Expression in the Prefrontal Cortex of the Rat

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

Clozapine, but not Haloperidol, Increases Brain Concentrations of Neuroactive Steroids in the Rat

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