Invited review Regulation of cell cycle and DNA repair in post-mitotic GABA neurons in psychotic disorders Francine M. Benes a, b, * a Program in Structural and Molecular Neuroscience, McLean Hospital,115 Mill Street, Belmont, MA 02478, USA b Department of Psychiatry (Neuroscience), Harvard Medical School, USA article info Article history: Received 22 October 2010 Received in revised form 24 November 2010 Accepted 15 December 2010 Keywords: GAD67 G1 G2 DNA polymerases DNA repair HDAC1 PAX5 Cyclin D2 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 neuro- psychiatric disorders. In schizophrenia and bipolar disorder, a network of genes involved in the regulation of GAD 67 , a marker for the functional differentiation of GABA cells, show pronounced changes in expression and include kainate receptor subunits, TGFb and Wnt signaling pathways, epigenetic factors and tran- scription 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 GAD 67 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 schizo- phrenia and bipolar disorder, suggesting that a common cell phenotype (in this case, decreased GAD 67 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’. Ó 2010 Published by Elsevier Ltd. 1. Introduction The fate of post-mitotic neurons in the adult brain is believed to be involved in the pathogenesis of neurodegenerative diseases of the central nervous system. Ectopic expression of cell cycle markers in post-mitotic cells of the adult brain is spatially and regionally well correlated with neuronal cell death and may be a common patho- physiological feature in many different adult brain disorders (Yang and Herrup, 2007). During normal embryogenesis, cell cycle regulation contributes to the proliferation of stem cells through mitotic divisions (Legrier et al., 2001); however, in post-mitotic cells, G1 arrest plays a direct role in establishing and maintaining their functional differ- entiation, unless abnormal conditions mitigate toward apoptosis (Sancar et al., 2004). It has recently been suggested that disturbances in cell cycle regulation may also play a role in disorders that are not neurodegenerative in nature (Benes, 2010). In psychotic disorders, recent evidence has suggested that a dys- regulation of inhibitory interneurons may involve decreased expression of the 67 kDalton isoform of glutamate decarboxylase (GAD 67 ), a marker for functional GABA neurons. A recent study has identified a network of genes involved in the regulation of GAD 67 expression in the adult hippocampus that includes cyclin D2 (Benes et al., 2007), a critical factor in cell cycle regulation (Zhao et al., 1995). In bipolar disorder, decreases in the expression of genes asso- ciated with cell cycle progression and the DNA damage response have been noted in GABA cells (Benes et al., 2009a,b). The discussion that follows explores the possibility that changes in the regulation of post- mitotic GABA cells in the adult hippocampus of subjects with psychotic disorders may help to determine the degree to which inhibitory interneurons, and their associated circuits, may be dysfunctional. 2. GAD 67 regulatory network Recent studies of psychotic disorders have revealed a significant decrease in the expression of transcripts for GAD 67 in the prefrontal cortex (Akbarian et al., 1995; Guidotti et al., 2000; Volk et al., 2000), anterior cingulate region (Woo et al., 2004,2007) and hippocampus (Benes et al., 2007). This has become one of the most replicated findings in postmortem studies of schizophrenia (SZ) and bipolar * Corresponding author. Program in Structural and Molecular Neuroscience, McLean Hospital,115 Mill Street, Belmont, MA 02478, USA. Tel.: þ1 617 855 2401; fax: þ1 617 855 3199. E-mail address: fbenes@mclean.harvard.edu. Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm 0028-3908/$ e see front matter Ó 2010 Published by Elsevier Ltd. doi:10.1016/j.neuropharm.2010.12.011 Neuropharmacology 60 (2011) 1232e1242