Site-specific regulation of cell cycle and DNA repair in post-mitotic GABA cells in schizophrenic versus bipolars

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-07, Vol.106 (28), p.11731-11736
• Main Authors: Benes, Francine M, Lim, Benjamin, Subburaju, Sivan
• Format: Article
• Language: English
• Subjects: Biological Sciences; Bipolar disorder; Bipolar Disorder - metabolism; Cell cycle; Cell Cycle - physiology; Cell cycle proteins; Cyclins; DNA damage; DNA repair; DNA Repair - physiology; Endodeoxyribonucleases - metabolism; gamma-Aminobutyric Acid - metabolism; Gene expression; Gene expression regulation; Gene Expression Regulation - physiology; Genes; Genetic loci; Genomics; Genotype & phenotype; Glutamate Decarboxylase - metabolism; Hippocampus - cytology; Humans; Neurons; Neurons - metabolism; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; Schizophrenia; Schizophrenia - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0903066106

GABA cell dysfunction in both schizophrenia (SZ) and bipolar disorder (BD) involves decreased GAD₆₇ expression, although this change involves fundamentally different networks of genes in the 2 disorders. One gene that is common to these 2 networks is cyclin D2, a key component of cell cycle regulation that shows increased expression in SZ, but decreased expression in BD. Because of the importance of cell cycle regulation in maintaining functional differentiation and DNA repair, the current study has examined the genes involved in the G₁ and G₂ checkpoints to generate new hypotheses regarding the regulation of the GABA cell phenotype in the hippocampus of SZ and BD. The results have demonstrated significant changes in cell cycle regulation in both SZ and BD and these changes include the transcriptional complex (TC) that controls the expression of E2F/DP-1 target genes critical for progression to G₂/M. The methyl-CpG binding domain protein (MBD4) that is pivotal for DNA repair, is significantly up-regulated in the stratum oriens (SO) of CA3/2 and CA1 in SZs and BDs. However, other genes associated with the TC, and the G₁ and G₂ checkpoints, show complex changes in expression in the SO of CA3/2 and CA1 of both SZs and BDS. Overall, the patterns of expression observed have suggested that the regulation of functional differentiation and/or genomic integrity of hippocampal GABA cells varies according to diagnosis and their location within the trisynaptic pathway.