Abstract Background Interneuron deficits are one of the most consistent findings in post-mortem studies of schizophrenia patients and are likely important in the cognitive deficits associated with schizophrenia. Disrupted-in-Schizophrenia 1 (DISC1), a strong susceptibility gene for schizophrenia and other mental illnesses, is involved in neurodevelopment, including that of interneurons. However, the mechanism by which DISC1 regulates interneuron development remains unknown. In this study, we analyzed interneuron histology in the Disc1 -L100P single point mutation mouse, that was previously shown to have behavioral abnormalities and cortical developmental defects related to schizophrenia. Results We sought to determine whether a Disc1 -L100P point mutation in the mouse would alter interneuron density and location. First, we examined interneuron position in the developing mouse cortex during embryonic days 14–16 as an indicator of interneuron tangential migration, and found striking migration deficits in Disc1 -L100P mutants. Further analysis of adult brains revealed that the Disc1 -L100P mutants have selective alterations of calbindin- and parvalbumin-expressing interneurons in the cortex and hippocampus, decreased GAD67/PV co-localization and mis-positioned interneurons across the neocortex when compared to wild-type littermates. Conclusion Our results are consistent with the anomalies seen in post-mortem schizophrenia studies and other Disc1 mutant mouse models. Future research is required to determine the specific mechanisms underlying these cellular deficits. Overall, these findings provide further evidence that DISC1 participates in interneuron development and add to our understanding of how DISC1 variants can affect susceptibility to psychiatric illness.
Disrupted-in-Schizophrenia 1 ( DISC1 ) is a strong candidate gene for schizophrenia and other mental disorders. DISC1 regulates neurodevelopmental processes including neurogenesis, neuronal migration, neurite outgrowth, and neurotransmitter signaling. Abnormal neuronal morphology and cortical architecture are seen in human postmortem brain from patients with schizophrenia. However, the etiology and development of these histological abnormalities remain unclear. We analyzed the histology of two Disc1 mutant mice with point mutations (Q31L and L100P) and found a relative reduction in neuron number, decreased neurogenesis, and altered neuron distribution compared to wild-type littermates. Frontal cortical neurons have shorter dendrites and decreased surface area and spine density. Overall, the histology of Disc1 mutant mouse cortex is reminiscent of the findings in schizophrenia. These results provide further evidence that Disc1 participates in cortical development, including neurogenesis and neuron migration.
There is strong evidence indicating neuroinflammation is an important mediator in multiple sclerosis (MS), with astrogliosis playing a significant role in this process. Surprisingly, astrocytes exert paradoxical roles during disease development, but the mechanisms remain unknown. Previously, we have reported that administering an interfering peptide (GluA2-G-Gpep) which specifically disrupts the GluA2-GAPDH interaction rescued neurological symptoms in the EAE mouse model of MS. In this study, we validated that the GluA2-GAPDH complex was elevated in LPS-induced primary reactive astrocytes, and GluA2-G-Gpep treatment significantly reduced GFAP expression levels in both EAE mice and reactive astrocytes. Further in vivo and in vitro analyses revealed that GluA2-G-Gpep administration normalized EAAT1 and EAAT2 expression, rescued compromised blood-brain barrier integrity via AQP4, promoted actin reorganization and changed mitochondrial dynamics. These alterations may partially be explained by changes in the nuclear GAPDH and p53 transcription pathways. Our findings provide critical implications for understanding the astrocyte properties regulated by GluA2-GAPDH associated with MS, and insights for novel treatment options targeting at astrocytes.
Schizophrenia is a devastating mental disorder, affecting almost 1% of the world population, and has a tremendous effect on social and occupational functioning. Dopamine D2 receptors (D2Rs) are the main targets of typical antipsychotic medications for schizophrenia, where they can effectively alleviate the positive symptoms by antagonizing D2Rs. Thus, investigating different modulation of D2R function is important in identifying novel drug targets and therapeutics for better outcomes in schizophrenia. Protein–protein interactions between D2Rs and other proteins are critical in regulating D2R signaling and subsequent downstream physiological functions. Here we described various biochemical methods including co-immunoprecipitation and protein affinity purification assays, that are commonly used to characterize D2R-associated protein complexes. Specifically, we reviewed the D2R–D1R and D2R–DISC1 interactions and discussed their association in the pathophysiology of schizophrenia. This chapter aims to provide systemic guidelines for the standard biochemical techniques in identifying D2R-associated protein–protein interactions, and to investigate the roles of these interactions in the brain.
Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by silencing of the FMR1 gene and subsequent loss of its protein product, fragile X retardation protein (FMRP). One of the most robust neuropathological findings in post-mortem human FXS and Fmr1 KO mice is the abnormal increase in dendritic spine densities, with the majority of spines showing an elongated immature morphology. However, the exact mechanisms of how FMRP can regulate dendritic spine development are still unclear. Abnormal dendritic spines can result from disturbances of multiple factors during neurodevelopment, such as alterations in neuron numbers, position and glial cells. In this study, we undertook a comprehensive histological analysis of the cerebral cortex in Fmr1 KO mice. They displayed significantly fewer neuron and PV-interneuron numbers, along with altered cortical lamination patterns. In terms of glial cells, Fmr1 KO mice exhibited an increase in Olig2-oligodendrocytes, which corresponded to the abnormally higher myelin expression in the corpus callosum. Iba1-microglia were significantly reduced but GFAP-astrocyte numbers and intensity were elevated. Using primary astrocytes derived from KO mice, we further demonstrated the presence of astrogliosis characterized by an increase in GFAP expression and astrocyte hypertrophy. Our findings provide important information on the cortical architecture of Fmr1 KO mice, and insights towards possible mechanisms associated with FXS.
The dopamine system modulates a diverse set of neural functions relevant to neuropsychiatric disorders and is modulated by some drugs used to treat these conditions. As a result, dopamine receptor genes have been a major focus for genetic studies that have analyzed putative associations between polymorphic variants and a wide range of clinical syndromes including alcoholism, substance abuse, schizophrenia, ADHD, anxiety disorders, bipolar and unipolar mood disorders, as well as related traits thought to contribute to these syndromes. In the following chapter, we review the basic genetic organization of the dopamine receptor genes and the evidence for association with these diagnoses. There is considerable inconsistency in the results from these genetic association studies, which is consistent with a complex genetic phenotype, and the neurobiological complexity of behaviors affected in neuropsychiatric illness. Overall, the strongest findings are the associations between variation in the DRD2 gene and alcoholism and the DRD4 gene and ADHD. While these associations do not suggest a major effect on risk in most patients, they do provide important insights into the pathophysiology of these disorders.
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