Transcription and pathway analysis of the superior temporal cortex and anterior prefrontal cortex in schizophrenia.

The molecular basis of schizophrenia is poorly understood; however, different brain regions are believed to play distinct roles in disease symptomology. We have studied gene expression in the superior temporal cortex (Brodmann area 22; BA22), which may play a role in positive pathophysiology, and compared our results with data from the anterior prefrontal cortex (BA10), which shows evidence for a role in negative symptoms. Genome-wide mRNA expression was determined in the BA22 region in 23 schizophrenics and 19 controls and compared with a BA10 data set from the same subjects. After adjustments for confounding sources of variation, we carried out GeneGO pathway enrichment analysis in each region. Significant differences were seen in age-related transcriptional changes between the BA22 and the BA10 regions, 21.8% and 41.4% of disease-associated transcripts showing age association, respectively. After removing age associated changes from our data, we saw the highest enrichment in processes mediating cell adhesion, synaptic contact, cytoskeletal remodelling, and apoptosis in the BA22 region. For the BA10 region, we observed the strongest changes in reproductive signalling, tissue remodelling, and cell differentiation. Further exploratory analysis also identified potentially disease-relevant processes that were undetected in our more stringent primary analysis, including autophagy in the BA22 region and the amyloid process in the BA10 region. Collectively, our analysis suggests disruption of many common pathways and processes underpinning synaptic plasticity in both regions in schizophrenia, whereas individual regions emphasize changes in certain pathways that may help to highlight pathway-specific therapeutic opportunities to treat negative or positive symptoms of the disease.

D1-like dopamine receptors regulate GABAA receptor function to modulate hippocampal neural progenitor cell proliferation.

The proliferation and differentiation of neural progenitor (NP) cells can be regulated by neurotransmitters including GABA and dopamine. The present study aimed to examine how these two neurotransmitter systems interact to affect post-natal hippocampal NP cell proliferation in vitro. Mouse hippocampal NP cells express functional GABAA receptors, which upon activation led to an increase in intracellular calcium levels via the opening of L-type calcium channels. Activation of these GABAA receptors also caused a significant decrease in proliferation; an effect that required the entry of calcium through L-type calcium channels. Furthermore, while activation of D1-like dopamine receptors had no effect on proliferation, it abrogated the suppressive effects of GABAA receptor activation on proliferation. The effects of D1-like dopamine receptors are associated with a decrease in the ability of GABAA receptors to increase intracellular calcium levels, and a reduction in the surface expression of GABAA receptors. In this way, D1-like dopamine receptor activation can increase the proliferation of NP cells by preventing GABAA receptor-mediated inhibition of proliferation. These results suggest that, in conditions where NP cell proliferation is under the tonic suppression of GABA, agonists which act through D1-like dopamine receptors may increase the proliferation of neural progenitors.