Relationship of GAD(67) regulation to cell cycle and DNA repair in GABA neurons in the adult hippocampus Bipolar disorder versus schizophrenia

Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 02/2010; 9(4):625-7. DOI: 10.4161/cc.9.4.10820
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Available from: Francine Benes, Nov 25, 2015
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    • "Typically, doses of pharmacological drugs prescribed during the last 3 to 6 months of life, or exposure at the time of death, are used to assess recent effects of drug exposure, in some cases in combination with data from toxicology (e.g. Benes et al., 2001; McNamara et al., 2008; Pantazopoulos et al., 2010; Cobb et al., 2013; Kunii et al., 2014; Shan et al., 2014). An advantage of this approach is that doses of drugs aimed at treating a psychiatric disorder are often lower during the last few months before death. "
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    ABSTRACT: Postmortem studies have reported decreased density and decreased gene expression of hippocampal interneurons in bipolar disorder, but neuroimaging studies of hippocampal volume and function have been inconclusive. To assess hippocampal volume, neuron number, and interneurons in the same specimens of subjects with bipolar disorder and healthy control subjects. Whole human hippocampi of 14 subjects with bipolar disorder and 18 healthy control subjects were cut at 2.5-mm intervals and sections from each tissue block were either Nissl-stained or stained with antibodies against somatostatin or parvalbumin. Messenger RNA was extracted from fixed tissue and real-time quantitative polymerase chain reaction was performed. Basic research laboratories at Vanderbilt University and McLean Hospital. Brain specimens from the Harvard Brain Tissue Resource Center at McLean Hospital. Volume of pyramidal and nonpyramidal cell layers, overall neuron number and size, number of somatostatin- and parvalbumin-positive interneurons, and messenger RNA levels of somatostatin, parvalbumin, and glutamic acid decarboxylase 1. The 2 groups did not differ in the total number of hippocampal neurons, but the bipolar disorder group showed reduced volume of the nonpyramidal cell layers, reduced somal volume in cornu ammonis sector 2/3, reduced number of somatostatin- and parvalbumin-positive neurons, and reduced messenger RNA levels for somatostatin, parvalbumin, and glutamic acid decarboxylase 1. Our results indicate a specific alteration of hippocampal interneurons in bipolar disorder, likely resulting in hippocampal dysfunction.
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    ABSTRACT: Disturbances of cell cycle regulation and DNA repair in post-mitotic neurons have been implicated in degenerative and malignant diseases of the human brain. Recent work is now suggesting that abnormal regulation of these functions in GABA cells of the adult hippocampus may also play a role in two neuropsychiatric disorders. In schizophrenia and bipolar disorder, a network of genes involved in the regulation of GAD₆₇, a marker for the functional differentiation of GABA cells, show pronounced changes in expression and include kainate receptor subunits, TGFβ and Wnt signaling pathways, epigenetic factors and transcription factors. One of these genes, cyclin D2, is involved in the regulation of cell cycle and DNA repair and appears to be a pivotal element in linking GAD₆₇ expression with these functional clusters of genes. Dysfunction of post-mitotic GABAergic neurons in the adult hippocampus of patients with psychotic disorders is associated with changes in the expression of genes that are involved in the maintenance of functional and genomic integrity of GABA cells. The nature of these changes is quite different in schizophrenia and bipolar disorder, suggesting that a common cell phenotype (in this case, decreased GAD₆₇ expression) may involve two fundamentally different molecular endophenotypes and reflect unique susceptibility genes involved in the respective disorders. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
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