Kerin K Higa | bioRxiv Science

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↗