Site-specific regulation of cell cycle and DNA repair in post-mitotic GABA cells in schizophrenic versus bipolars.
GABA cell dysfunction in both schizophrenia (SZ) and bipolar disorder (BD) involves decreased GAD(67) 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 G(1) and G(2) 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 G(2)/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 G(1) and G(2) 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.
Benes
Francine M
FM
Program in Structural and Molecular Neuroscience, McLean Hospital, Belmont, MA 02478, USA. fbenes@mclean.harvard.edu
Lim
Benjamin
B
Subburaju
Sivan
S
D001714:Bipolar Disorder / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology; D004706:Endodeoxyribonucleases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012559:Schizophrenia / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D005680:gamma-Aminobutyric Acid; D004706:Endodeoxyribonucleases; C118712:MBD4 protein, human; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1