Cognitive functioning and GABAA/benzodiazepine receptor binding in schizophrenia: A 1231-iomazenil SPET study

Probing GABA Receptor Function in Schizophrenia with Iomazenil

“…Converging lines of evidence, including postmortem (Benes, 2000;Benes and Berretta, 2001;Benes et al, 1996;Hashimoto et al, 2003;Lewis et al, 2005;Ohnuma et al, 1999;Volk et al, 2000;Woo et al, 1998), genetic (reviewed by Charych et al (2009), and brain imaging studies (Ball et al, 1998;Busatto et al, 1997;Schroder et al, 1997;Verhoeff et al, 1999;Yoon et al, 2010), suggest that dysfunction of the gamma-amino butyric acid (GABA) system contributes to the pathophysiology of schizophrenia. In postmortem studies of schizophrenic patients, alterations in GABAergic transmission have been shown in many ways, including (1) reduced mRNA levels for the GABA-synthesizing enzyme glutamic acid decarboxylase-67 (Impagnatiello et al, 1998;Volk et al, 2000), (2) decreased density of axon cartridges of chandelier neurons (Woo et al, 1998), (3) decreased gene expression of the GABA membrane transporter-1 (Ohnuma et al, 1999;, (4) increased density of GABA-A receptors (Benes et al, 1996), (5) elevated density of a 1 - (Impagnatiello et al, 1998;Ohnuma et al, 1999) and a 2 -subunit-containing GABA-A receptors at pyramidal neuron axon segments , (6) decreased Reelin mRNA, which is preferentially expressed in GABAergic interneurons (Impagnatiello et al, 1998), and (7) decreased levels of ankyrin-G, a membrane protein that anchors the GABA receptor complex onto initial axonal segments of pyramidal cells in the area of chandelier cell synapses in superficial cortical area (Cruz et al, 2009).…”

“…Many of these findings appear to be specific to schizophrenia . Besides post-mortem data, some in vivo brain imaging (SPECT) studies suggest reduced benzodiazepine (BZ) receptor binding in schizophrenia (Ball et al, 1998;Busatto et al, 1997;Schroder et al, 1997).…”

Role of GABA Deficit in Sensitivity to the Psychotomimetic Effects of Amphetamine

“…Converging lines of evidence, including postmortem (Benes, 2000;Benes and Berretta, 2001;Hashimoto et al, 2003;Lewis et al, 2005;Ohnuma et al, 1999;Volk et al, 2000;Volk and Lewis, 2002a;Volk et al, 2002b;Woo et al, 1998), genetic (reviewed by Cherlyn et al (2010)), and brain imaging studies (Ball et al, 1998;Busatto et al, 1997;Kegeles et al, 2012;Ongur et al, 2010;Schroder et al, 1997;Verhoeff et al, 1999;Yoon et al, 2010), suggest that the dysfunction of the GABA system may contribute to the pathophysiology of schizophrenia. The results of in vivo magnetic resonance spectroscopy studies are mixed with some studies reporting elevations (Kegeles et al, 2012;Ongur et al, 2010), reductions (Rowland et al, 2013;Yoon et al, 2010) or no differences (Goto et al, 2009;Tayoshi et al, 2010) in GABA levels in specific brain regions of schizophrenia patients relative to controls.…”

“…The results of in vivo magnetic resonance spectroscopy studies are mixed with some studies reporting elevations (Kegeles et al, 2012;Ongur et al, 2010), reductions (Rowland et al, 2013;Yoon et al, 2010) or no differences (Goto et al, 2009;Tayoshi et al, 2010) in GABA levels in specific brain regions of schizophrenia patients relative to controls. Some, but not all, in vivo receptor imaging studies suggest reduced benzodiazepine receptor binding in schizophrenia (Ball et al, 1998;Busatto et al, 1997;Schroder et al, 1997;Verhoeff et al, 1999). Several post-mortem studies have revealed evidence of pre-and postsynaptic abnormalities in specific GABAergic interneurons, namely the parvalbumin-positive basket cells, resulting in a reduction in the inhibitory control of pyramidal cells (Lewis et al, 2012;Lewis et al, 2005).…”

Association between GABA-A Receptor Alpha 5 Subunit Gene Locus and Schizophrenia of a Later Age of Onset

“…Among other neurotransmitters, Á-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, is also postulated to play a role in the neurobiological basis of schizophrenia according to the hypothesis that an imbalance between dopaminergic and GABAergic neuronal activity is related to the manifestation of the disorder [4,5]. Indeed, abnormalities of the GABAergic function can precipitate psychotic symptomatology, the GABA tone is changed by chronic antipsychotic administration, reduced GABA-A/benzodiazepine receptor binding was found to be associated with symptom score severity and cognitive decline in schizophrenia, and aberrations in the GABAergic activity of the prefrontal and singulate cortices as well as the hippocampal formation have been found in schizophrenic patients [6][7][8][9][10][11]. Since the main receptor for GABA in the central nervous system is GABA-A, the genes of this receptor's subunits can be considered as candidate genes for schizophrenia.…”