| 1 | Proc. Natl. Acad. Sci. U.S.A. 2013 Oct 110: 17552-7 |
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| PMID | 24101523 |
| Title | Deficits in microRNA-mediated Cxcr4/Cxcl12 signaling in neurodevelopmental deficits in a 22q11 deletion syndrome mouse model. |
| Abstract | 22q11 deletion syndrome (22q11DS) frequently accompanies psychiatric conditions, some of which are classified as schizophrenia and bipolar disorder in the current diagnostic categorization. However, it remains elusive how the chromosomal microdeletion leads to the mental manifestation at the mechanistic level. Here we show that a 22q11DS mouse model with a deletion of 18 orthologous genes of human 22q11 (Df1/+ mice) has deficits in migration of cortical interneurons and hippocampal dentate precursor cells. Furthermore, Df1/+ mice show functional defects in Chemokine receptor 4/Chemokine ligand 12 (Cxcr4/CXCL12; Sdf1) signaling, which reportedly underlie interneuron migration. Notably, the defects in interneuron progenitors are rescued by ectopic expression of Dgcr8, one of the genes in 22q11 microdeletion. Furthermore, heterozygous knockout mice for Dgcr8 show similar neurodevelopmental abnormalities as Df1/+ mice. Thus, Dgcr8-mediated regulation of microRNA is likely to underlie Cxcr4/CXCL12 signaling and associated neurodevelopmental defects. Finally, we observe that expression of CXCL12 is decreased in olfactory neurons from sporadic cases with schizophrenia compared with normal controls. Given the increased risk of 22q11DS in schizophrenia that frequently shows interneuron abnormalities, the overall study suggests that CXCR4/CXCL12 signaling may represent a common downstream mediator in the pathophysiology of schizophrenia and related mental conditions. |
| SCZ Keywords | schizophrenia |
| 2 | Neurosci Biobehav Rev 2014 May 42: 93-115 |
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| PMID | 24513303 |
| Title | Chemokines and chemokine receptors in mood disorders, schizophrenia, and cognitive impairment: a systematic review of biomarker studies. |
| Abstract | The search for immune biomarkers in psychiatric disorders has primarily focused on pro-inflammatory cytokines. Other immune proteins including chemokines have been relatively neglected in such studies. Recent evidence has implicated chemokines in many neurobiological processes potentially relevant to psychiatric disorders, beyond their classical chemotactic functions. These may include neuromodulator effects, neurotransmitter-like effects, and direct/indirect regulation of neurogenesis. This systematic review presents the existing early evidence which supports an association of many chemokines with the psychiatric disorders: depression, bipolar disorder, schizophrenia, mild cognitive impairment and Alzheimer's disease. The non-specific association of chemokines including CXCL8 (IL-8), CCL2 (MCP-1), CCL3 (MIP-1?) and CCL5 (RANTES) with these disorders across diagnostic categories implies a generalised involvement of many chemokine systemic with psychiatric disease. Additional chemokines with great mechanistic relevance including CXCL12 (SDF-1) and CX3CL1 (fractalkine) have been rarely reported in the existing human literature and should be included in future clinical studies. The potential utility of these proteins as pathologically relevant biomarkers or therapeutic targets should be considered by future clinical and translational research. |
| SCZ Keywords | schizophrenia |
| 3 | Neurosci. Res. 2016 Apr 105: 75-9 |
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| PMID | 26458529 |
| Title | Increased stereotypy in conditional Cxcr4 knockout mice. |
| Abstract | Chemokines play important roles in the central nervous system, including mediating neuroinflammation and guiding the intracortical migration of interneurons during development. Alteration in parvalbumin-positive interneurons is a key neuropathological hallmark of multiple mental conditions. We recently reported a significant reduction in the expression of CXCL12 in olfactory neurons from sporadic cases with schizophrenia compared with matched controls, suggesting a role for CXCR4/CXCL12 signaling in mental conditions. Thus, we depleted the chemokine receptor Cxcr4 from mice using the parvalbumin-2A-Cre line. The conditional knockout mice exhibited a unique behavioral phenotype involving increased stereotypy. Stereotypy is observed in many psychiatric conditions, including schizophrenia, autism, and dementia. Thus, the Cxcr4 conditional knockout mice may serve as a model for this symptomatic feature. |
| SCZ Keywords | schizophrenia |