| 1 | Proc. Natl. Acad. Sci. U.S.A. 2012 Nov 109: 18601-6 |
|---|---|
| PMID | 23091025 |
| Title | Cxcr4 regulation of interneuron migration is disrupted in 22q11.2 deletion syndrome. |
| Abstract | Interneurons are thought to be a primary pathogenic target for several behavioral disorders that arise during development, includingschizophreniaand autism. It is not known, however, whether genetic lesions associated with these diseases disrupt established molecular mechanisms of interneuron development. We found that diminished 22q11.2 gene dosage-the primary genetic lesion in 22q11.2 deletion syndrome (22q11.2 DS)-specifically compromises the distribution of early-generated parvalbumin-expressing interneurons in the Large Deletion (LgDel) 22q11.2DS mouse model. This change reflects cell-autonomous disruption of interneuron migration caused by altered expression of the cytokine C-X-C chemokine receptor type 4 (CXCR4), an established regulator of this process.CXCR4is specifically reduced in LgDel migrating interneurons, and genetic analysis confirms that diminishedCXCR4alters interneuron migration in LgDel mice. Thus, diminished 22q11.2 gene dosage disrupts cortical circuit development by modifying a critical molecular signaling pathway viaCXCR4that regulates cortical interneuron migration and placement. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Proc. Natl. Acad. Sci. U.S.A. 2013 Oct 110: 17552-7 |
| 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 asschizophreniaand 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;据说underli Sdf1)信号e 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 underlieCXCR4/Cxcl12 signaling and associated neurodevelopmental defects. Finally, we observe that expression of CXCL12 is decreased in olfactory neurons from sporadic cases withschizophreniacompared with normal controls. Given the increased risk of 22q11DS inschizophreniathat frequently shows interneuron abnormalities, the overall study suggests thatCXCR4/CXCL12 signaling may represent a common downstream mediator in the pathophysiology ofschizophreniaand related mental conditions. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Front Neurosci 2015 -1 9: 74 |
| PMID | 25805966 |
| Title | Neuronal migration abnormalities and its possible implications for schizophrenia. |
| Abstract | schizophreniais a complex mental disorder that displays behavioral deficits such as decreased sensory gating, reduced social interaction and working memory deficits. The neurodevelopmental model is one of the widely accepted hypotheses of the etiology ofschizophrenia. Subtle developmental abnormalities of the brain which stated long before the onset of clinical symptoms are thought to lead to the emergence of illness.schizophrenia有很强的遗传因素,但其底层molecular pathogenesis is still poorly understood. Genetic linkage and association studies have identified several genes involved in neuronal migrations as candidate susceptibility genes forschizophrenia, although their effect size is small. Recent progress in copy number variation studies also has identified much higher risk loci such as 22q11. Based on these genetic findings, we are now able to utilize genetically-defined animal models. Here we summarize the results of neurodevelopmental and behavioral analysis of genetically-defined animal models. Furthermore, animal model experiments have demonstrated that embryonic and perinatal neurodevelopmental insults in neurogenesis and neuronal migrations cause neuronal functional and behavioral deficits in affected adult animals, which are similar to those ofschizophrenicpatients. However, these findings do not establish causative relationship. Genetically-defined animal models are a critical approach to explore the relationship between neuronal migration abnormalities and behavioral abnormalities relevant toschizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Front Neurosci 2015 -1 9: 74 |
| PMID | 25805966 |
| Title | Neuronal migration abnormalities and its possible implications for schizophrenia. |
| Abstract | schizophreniais a complex mental disorder that displays behavioral deficits such as decreased sensory gating, reduced social interaction and working memory deficits. The neurodevelopmental model is one of the widely accepted hypotheses of the etiology ofschizophrenia. Subtle developmental abnormalities of the brain which stated long before the onset of clinical symptoms are thought to lead to the emergence of illness.schizophrenia有很强的遗传因素,但其底层molecular pathogenesis is still poorly understood. Genetic linkage and association studies have identified several genes involved in neuronal migrations as candidate susceptibility genes forschizophrenia, although their effect size is small. Recent progress in copy number variation studies also has identified much higher risk loci such as 22q11. Based on these genetic findings, we are now able to utilize genetically-defined animal models. Here we summarize the results of neurodevelopmental and behavioral analysis of genetically-defined animal models. Furthermore, animal model experiments have demonstrated that embryonic and perinatal neurodevelopmental insults in neurogenesis and neuronal migrations cause neuronal functional and behavioral deficits in affected adult animals, which are similar to those ofschizophrenicpatients. However, these findings do not establish causative relationship. Genetically-defined animal models are a critical approach to explore the relationship between neuronal migration abnormalities and behavioral abnormalities relevant toschizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Schizophr. Res. 2015 Sep 167: 12-7 |
| PMID | 25464914 |
| Title | Chemokine receptors and cortical interneuron dysfunction in schizophrenia. |
| Abstract | Alterations in inhibitory (GABA) neurons, including deficiencies in the GABA synthesizing enzyme GAD67, in the prefrontal cortex inschizophreniaare pronounced in the subpopulations of neurons that contain the calcium-binding protein parvalbumin or the neuropeptide somatostatin. The presence of similar illness-related deficits in the transcription factor Lhx6, which regulates prenatal development of parvalbumin and somatostatin neurons, suggests that cortical GABA neuron dysfunction may be related to disturbances in utero. Since the chemokine receptorsCXCR4and CXCR7 guide the migration of cortical parvalbumin and somatostatin neurons from their birthplace in the medial ganglionic eminence to their final destination in the neocortex, we sought to determine whether alteredCXCR4and/or CXCR7 mRNA levels were associated with disturbances in GABA-related markers inschizophrenia. Quantitative PCR was used to quantifyCXCR4and CXCR7 mRNA levels in the prefrontal cortex of 62schizophreniaand 62 healthy comparison subjects that were previously characterized for markers of parvalbumin and somatostatin neurons and in antipsychotic-exposed monkeys. We found elevated mRNA levels for CXCR7 (+29%; p<.0001) andCXCR4(+14%, p=.052) inschizophreniasubjects but not in antipsychotic-exposed monkeys. CXCR7 mRNA levels were inversely correlated with mRNA levels for GAD67, parvalbumin, somatostatin, and Lhx6 inschizophreniabut not in healthy subjects. These findings suggest that higher mRNA levels for CXCR7, and possiblyCXCR4, may represent a compensatory mechanism to sustain the migration and correct positioning of cortical parvalbumin and somatostatin neurons in the face of other insults that disrupt the prenatal development of cortical GABA neurons inschizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Nord J Psychiatry 2016 Feb -1: 1-6 |
| PMID | 26906930 |
| Title | Chemokine gene variants in schizophrenia. |
| Abstract | Background Chemokines are known to play a major role in driving inflammation and immune responses in several neuroinflammatory diseases, including multiple sclerosis, Alzheimer's disease and Parkinson's disease. Inflammation has also been implicated in the pathogenesis ofschizophrenia. Aim We aimed to investigate a potential link between chemokines andschizophreniaand analyze the role of MCP-1-A2518G, SDF-1-3'A, CCR5-delta32, CCR5-A55029G,CXCR4-C138T and CCR2-V64I gene polymorphisms in the Turkish population. Methods Genotyping was conducted by PCR-RFLP based on 140 patients and 123 unrelated healthy controls to show the relation between chemokine gene variants andschizophreniarisk. Results Frequencies of CCR5-A55029G A genotypes and CCR5-A55029G AG genotypes were found higher in patients than the controls and even also CCR2-V64I WT: CCR5-A55029G A and CCR2-V64I 64I: CCR5-A55029G A haplotypes significantly associated according to Bonferroni correction. However, no significant association was found for any of the other polymorphisms with the risk ofschizophrenia. Conclusions Our findings suggest that CCR5-A55029G polymorphisms and CCR2-V64I WT: CCR5-A55029G A and CCR2-V64I 64I: CCR5-A55029G A haplotypes might have association withschizophreniapathogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Neurosci. Res. 2016 Apr 105: 75-9 |
| 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 withschizophreniacompared with matched controls, suggesting a role forCXCR4/CXCL12 signaling in mental conditions. Thus, we depleted the chemokine receptorCXCR4from 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, includingschizophrenia, autism, and dementia. Thus, theCXCR4conditional knockout mice may serve as a model for this symptomatic feature. |
| SCZ Keywords | schizophrenia, schizophrenic |