M174. REDUCED CHEMOKINE SIGNALLING CAPACITY IS ASSOCIATED WITH INHIBITORY INTERNEURON DYSFUNCTION IN SUBCORTICAL BRAIN REGIONS IN SCHIZOPHRENIA AND BIPOLAR DISORDER
Authors: Weissleder Christin , Webster Maree J , Shannon Weickert Cynthia 
Published: May 2020

Abstract

Background
The subependymal zone (SEZ) adjacent to the lateral ventricles represents the largest reservoir of postnatally-generated cortical and striatal inhibitory interneurons in the human brain. Expression of markers representing the generation of neuronal progenitors from neural stem cells is reduced in the adult SEZ in schizophrenia and bipolar disorder; however, underlying mechanisms and relationships to inhibitory interneuron dysfunction remain unknown. Stem cell maintenance, neuronal migration and cell survival are regulated by signaling of the CXC motif chemokine 12 (CXCL12) through CXC motif chemokine receptors 4 (CXCR4) and 7 (CXCR7), which are increasingly implicated in the pathophysiology of psychiatric disorders.

Methods
Post-mortem tissue was obtained from 33 schizophrenia, 32 bipolar disorder and 33 control cases from the Stanley Medical Research Institute. SEZ and caudate nucleus tissue was dissected from 60 µm sections for RNA isolation and cDNA synthesis. Gene expression of CXCL12, CXCR4 and CXCR7 were determined by quantitative polymerase chain reactions. Semi-partial correlations were performed to assess whether CXC chemokine family member mRNAs may correlate with markers of neural stem cells (PROM1, GFAPD), neuronal progenitors (SOX2, ASCL1) and inhibitory interneurons (CALB2, NPY) in the SEZ and caudate nucleus.

Results
In the SEZ, CXCL12 mRNA was decreased in schizophrenia compared to controls and bipolar disorder (14–24%, all p≤0.03). CXCR4 and CXCR7 mRNAs were both decreased in schizophrenia and bipolar disorder compared to controls (9–33%, all p≤0.05). CXCL12, CXCR4 and CXCR7 expression positively correlated with PROM1, GFAPD, SOX2 and ASCL1 mRNAs (0.28≥sr≤0.61). In the caudate nucleus, CXCL12 mRNA was decreased in schizophrenia and bipolar disorder compared to controls (19–26%, all p≤0.05). CXCR4 mRNA was decreased in schizophrenia compared to controls (20%, p=0.01), while CXCR7 expression did not significantly differ across diagnostic groups. CALB2 and NPY mRNAs were increased in bipolar disorder compared to controls (13–27%, all p≤0.05). CXCR4 expression positively correlated with CALB2 mRNA (sr=0.26), while CXCR7 expression negatively correlated with NPY mRNA (sr=0.26).

Discussion
These findings provide the first molecular evidence of decreased CXC chemokine family member expression in the SEZ and caudate nucleus in psychiatric disorders, with exacerbated deficits in schizophrenia compared to bipolar disorder. Dysregulated CXC chemokine family member expression may hamper neural stem cell maintenance and neuronal differentiation, which may contribute to inhibitory interneuron dysfunction in psychiatric disorders. Future work will determine the cellular localisation of CXCR4 and CXCR7 expression in the SEZ and caudate nucleus to disentangle the regulatory role of CXCL12 signalling in the generation, migration and survival of inhibitory interneurons in the human brain.