Biology subjects

Xianjin Zhou

Publications and source records attributed to Xianjin Zhou.

4 recordsLinked to original sources

bioRxiv2015

Restoration of Sp4 in forebrain GABAergic neurons rescues hypersensitivity to ketamine in Sp4 hypomorphic mice

Ketamine produces schizophrenia-like behavioral phenotypes in healthy people. Prolonged ketamine effects and exacerbation of symptoms were observed in schizophrenia patients after administration of ketamine. More recently, ketamine has been used as a potent antidepressant to treat patients with major depression. The genes and neurons that regulate behavioral responses to ketamine, however, remain poorly understood. Our previous studies found that Sp4 hypomorphic mice displayed several behavioral phenotypes relevant to psychiatric disorders, consistent with human SP4 gene associations with schizophrenia, bipolar, and major depression. Among those behavioral phenotypes, hypersensitivity to ketamine-induced hyperlocomotion has been observed in Sp4 hypomorphic mice. Here, we report differential genetic restoration of Sp4 expression in forebrain excitatory neurons or GABAergic neurons in Sp4 hypomorphic mice and the effects of these restorations on different behavioral phenotypes. Restoration of Sp4 in forebrain excitatory neurons did not rescue deficient sensorimotor gating, fear learning, or ketamine-induced hyperlocomotion. Restoration of Sp4 in forebrain GABAergic neurons, however, rescued ketamine-induced hyperlocomotion, but did not rescue deficient sensorimotor gating or fear learning. Our studies suggest that the Sp4 gene in forebrain GABAergic neurons plays an essential role in regulating some behavioral responses to ketamine.

Neuroscience↗

bioRxiv2014

Abnormal X Chromosome Inactivation in Females with Major Psychiatric Disorders

Bipolar disorder, major depression and schizophrenia are severe brain disorders. No biological hallmark has been identified for any of these disorders. Here, we report that abnormal X chromosome inactivation (XCI) often presents in lymphoblastoid cells of female patients with different major psychiatric disorders in the general population. X chromosome inactivation is well preserved in human lymphoblastoid cells. XIST, KDM5C, and other X-linked genes are over-expressed in the lymphoblastoid cells of female patients, suggesting an abnormal XCI. Trimethylation of lysine 27 on histone 3 (H3K27me3) is significantly increased at both XIST and KDM5C gene loci. We found that XIST and KDM5C expression can be used as a potential diagnostic hallmark for major psychiatric disorders in a large sub-population of female patients. Preliminary studies also suggest an increased XIST expression in postmortem brains from female patients with schizophrenia, bipolar disorder, and major depression. An increased gene dosage from some X-linked genes may contribute to the development of psychiatric disorders, as functional disomy of partial X chromosome have been suggested to cause mental retardation and other developmental abnormalities. Additionally, patients with Klinefelter syndrome (XXY) or Triple X syndrome (XXX) frequently display psychiatric disorders due to an extra X chromosome. Mutation of the KDM5C gene was reported to cause X-linked syndromic mental retardation. Our studies suggest that abnormal X chromosome inactivation could play a causal role in development of major psychiatric disorders in females. Correction of abnormal X chromosome inactivation may prevent and/or cure major psychiatric disorders in a sub-population of female patients in the future.

Neuroscience↗

bioRxiv2014

Inhibition of protein translation by the DISC1-Boymaw fusion gene from a Scottish family with major psychiatric disorders

The t(1; 11) translocation appears to be the causal genetic lesion with 70% penetrance for schizophrenia, major depression, and other psychiatric disorders in a Scottish family. Molecular studies identified the disruption of the DISC1 (disrupted-in-schizophrenia 1) gene by chromosome translocation at chromosome 1q42. Our previous studies, however, revealed that the translocation also disrupted another gene, Boymaw (also termed DISC1FP1), on chromosome 11. After translocation, two fusion genes (the DISC1-Boymaw (DB7) and the Boymaw-DISC1 (BD13)) are generated between the DISC1 and Boymaw genes. In the present study, we report that expression of the DB7 fusion gene inhibits both intracellular NADH oxidoreductase activities and protein translation. We generated humanized DISC1-Boymaw mice with gene targeting to examine the in vivo functions of the fusion genes. Consistent with the in vitro studies on the DB7 fusion gene, protein translation activity is decreased in the hippocampus and in cultured primary neurons from the brains of the humanized mice. Expression of Gad67, Nmdar1, and Psd95 proteins are also reduced. The humanized mice display prolonged and increased responses to the NMDA receptor antagonist, ketamine, on various mouse genetic backgrounds. Abnormal information processing of acoustic startle and depressive-like behaviors are also observed. In addition, the humanized mice display abnormal erythropoiesis, which was reported to associate with depression in humans. Expression of the DB7 fusion gene may reduce protein translation to impair brain functions and thereby contribute to the pathogenesis of major psychiatric disorders.

Neuroscience↗

bioRxiv2014

Boymaw, Overexpressed in Brains with Major Psychiatric Disorders, May Encode a Small Protein to Inhibit Mitochondrial Function and Protein Translation

The t(1,11) chromosome translocation co-segregates with major psychiatric disorders in a large Scottish family. The translocation disrupts the DISC1 and Boymaw (DISC1FP1) genes on chromosomes 1 and 11, respectively. After translocation, two fusion genes are generated. Our recent studies found that the DISC1-Boymaw fusion protein is localized in mitochondria and inhibits oxidoreductase activity, rRNA expression, and protein translation. Mice carrying the DISC1-Boymaw fusion genes display intermediate behavioral phenotypes related to major psychiatric disorders. Here, we report that the Boymaw gene encodes a small protein predominantly localized in mitochondria. The Boymaw protein inhibits oxidoreductase activity, rRNA expression, and protein translation in the same way as the DISC1-Boymaw fusion protein. Interestingly, Boymaw expression is up-regulated by different stressors at RNA and/or protein translational levels. In addition, we found that Boymaw RNA expression is significantly increased in the postmortem brains of patients with major psychiatric disorders. Our studies therefore suggest that the Boymaw gene is a potential susceptibility gene for major psychiatric disorders in both the Scottish t(1,11) family and the general population of patients.

Neuroscience↗