Robinson et al.

DGCR2, a schizophrenia risk gene, regulates synaptic transmission, anxiety and hippocampal-prefrontal synchrony

Heath Robinson, Bin Luo, Wenbing Chen, Zhibing Tan, Lin Mei

Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH

Chromosome 22q11.2 deletion syndrome is due to a common deletion in this chromosomal region that causes an array of developmental defects including DiGeorge syndrome and velocardiofacial syndrome. Chromosome 22q11.2 deletion syndrome is the most common microdeletion syndrome (1 in approximately 4000 births), containing a 30 megabase region with 46 genes. DGCR2 (DiGeorge Syndrome Critical Region Gene 2) is one of these gene and its’ expression is also reduced in schizophrenic patients. Schizophrenia, a mental disorder affecting 1% of the population, and chromosome 22q11.2 deletion syndrome possess a large amount of comorbidity. For instance, 1% of Schizophrenia patients possess Chromosome 22q11.2 microdeletion syndrome, whereas up to 30% of Chromosome 22q11.2 syndrome patients display symptoms diagnosable of Schizophrenia. DGCR2 encodes for 550-amino acid putative adhesion protein, yet, its’ exact physiological function in the brain remains unclear. To address this, we generated DGCR2 deficient mice DGCR2-LacZ (LacZ/LacZ) where the DGCR2 gene is replaced by a cassette containing lacZ. We found that the β-galactosidase activity was detectable in a number of regions in the mouse brain, with abundant expression in the hippocampus (HPC) and cortex. Using immunostaining with anti-DGCR2 antibody, we found that DGCR2 was expressed in pyramidal neurons and is co-localized to PSD-95 puncta at the synapses. Furthermore, mEPSC frequency, but not amplitude was reduced in HPC region of DGCR2 deficient mice, yet, mIPSCs and Paired Pulse Ratio was left unchanged. DGCR2 deficient mice exhibited anxiety-like symptoms in the Open Field Test (OFT) and Elevated Plus Maze (EPM), by a decreased time spent in the center and open arms, respectively. This anxiety-like phenotype is intriguing as 40-70% of Chromosome 22q11.2 deletion syndrome and around 40% of Schizophrenia patients suffer from anxiety disorders. Synchronized neural activity between the HPC and prefrontal cortex (PFC) has not only shown to be involved in anxiety-like behavior, but disrupted in mouse models of Chromosome 22q11.2 deletion syndrome and Schizophrenia. To test this, we inserted electrodes into the HPC and PFC and recorded in vivo during the OFT and EPM. Interestingly, we found a decrease in synchronous activity between the HPC and PFC during OFT and EPM, especially in the anxiogenic portions of the behavior. Our study reveals novel function of DGCR2, specifically its importance to excitatory transmission and HPC-PFC synchrony that might underlie the pathology of anxiety disorders, Chromosome 22q11.2 deletion syndrome and Schizophrenia.