Shin ichi Kano

Adolescent Stress–Induced Epigenetic Control of Dopaminergic Neurons via Glucocorticoids

Defeat, Distress, and Glucocorticoids Understanding how individuals control emotions and cope with stressful events is a major clinical concern and of importance for the treatment of psychiatric illnesses (see the Perspective by McEwen). Barik et al. (p. 332) discovered that aggressive defeat stress in mice caused glucocortioid release and increased activity in the dopamine system. Deleting the glucocorticoid receptors in dopaminoceptive neurons completely prevented the social avoidance that usually follows aggressive defeat. How the combination of genetic factors and environmental stressors during adolescence determines adult behavior and how their disturbance results in neuropsychiatric disorders is poorly understood. Niwa et al. (p. 335) found that isolation stress during adolescence, which does not cause any long-lasting changes in wild-type mice, induced significant neurochemical and behavioral alterations in mutant mice expressing a dominant-negative variant of the disrupted in schizophrenia 1 gene under the control of the prion protein promoter. These deficits could be reversed by a glucocorticoid receptor antagonist. Genetically susceptible mice isolated during adolescence can subsequently present schizophrenia-like symptoms. [Also see Perspective by McEwen] Environmental stressors during childhood and adolescence influence postnatal brain maturation and human behavioral patterns in adulthood. Accordingly, excess stressors result in adult-onset neuropsychiatric disorders. We describe an underlying mechanism in which glucocorticoids link adolescent stressors to epigenetic controls in neurons. In a mouse model of this phenomenon, a mild isolation stress affects the mesocortical projection of dopaminergic neurons in which DNA hypermethylation of the tyrosine hydroxylase gene is elicited, but only when combined with a relevant genetic risk for neuropsychiatric disorders. These molecular changes are associated with several neurochemical and behavioral deficits that occur in this mouse model, all of which are blocked by a glucocorticoid receptor antagonist. The biology and phenotypes of the mouse models resemble those of psychotic depression, a common and debilitating psychiatric disease.

Genome-wide profiling of multiple histone methylations in olfactory cells: further implications for cellular susceptibility to oxidative stress in schizophrenia

Genome-wide profiling of multiple histone methylations in olfactory cells: further implications for cellular susceptibility to oxidative stress in schizophrenia

Marked reduction of soluble superoxide dismutase-1 (SOD1) in cerebrospinal fluid of patients with recent-onset schizophrenia

Recent schizophrenia research supports a model wherein aberrant brain changes in late-adolescence contribute to the onset and early progression of disease.1 To further examine this model, longitudinal studies of genetic high-risk subjects, including those in prodromal stage, have recently been conducted.2 Parallel studies evaluating patients with recent-onset schizophrenia are growing in number.3 Nonetheless, almost all these studies are limited to clinical and neuropsychological characterization, and to brain imaging. Therefore, the molecular mechanisms underlying these dynamic changes remain elusive. In order to address this fundamental question with better molecular understanding, we have examined the cerebrospinal fluid (CSF) from patients with recent-onset schizophrenia (within the first five years of disease) and have compared these samples to those from age-matched healthy controls and patients with chronic schizophrenia (five or more years of schizophrenia) (Supplementary Table 1). Building on the hypothesis that oxidative stress and associated neuroinflammatory response may play a role in this dynamic process,4 we measured the levels of 14 selected molecules (Supplementary Table 2). Here we report the novel finding of a dramatically reduced level of soluble superoxide dismutase-1 (SOD1) in CSF from patients with recent-onset schizophrenia in contrast to samples from age-matched healthy controls (Table 1, Supplementary Figure 1). Furthermore, the level of CSF soluble SOD1 from recent-onset patients is lower than that from patients with chronic schizophrenia. To our knowledge, this is the first report of decreased CSF SOD1 in recent-onset schizophrenia. We also highlight that while the sample size of patients with one year or less disease is small, the absolute concentrations of soluble SOD1 are most robustly decreased in this cohort. We speculate that the decrease in soluble SOD1 between patients with one year or less disease and age-matched healthy controls is limited in significance by the small sample size. Table 1 Comparison of CSF soluble SOD1 concentration between patients with recent-onset schizophrenia (less than five years disease) grouped by disease duration and age-matched healthy controls. While our reported observations require replication in a larger sample, this study implies two innovative conceptual contributions. First, the reduction of soluble SOD1 may directly underlie oxidative stress at the onset of schizophrenia through decreased availability of this important antioxidant enzyme. We further note that this decrease in CSF soluble SOD1 concentration could be a secondary effect of another pro-oxidative process. Nevertheless, this ultimate decrease in soluble SOD1 is likely to facilitate overall oxidative stress. Thus, we provide further evidence of the “oxidative stress hypothesis” in schizophrenia. Second, we note the possibility that a decrease in CSF soluble SOD1 may reflect an increase in “insoluble” SOD1. This is analogous to decreased Aβ1-42 in CSF from patients with Alzheimer’s disease reflecting insoluble Aβ1-42 and senile plaques.5 Likewise, SOD1 is amyloidogenic and can be associated with brain disorders, such as amyotrophic lateral sclerosis (ALS).6 We wish to recall that aggregate formation in Huntington’s disease and other brain disorders has been discovered only after specific probing of target molecules, such as Huntingtin detection using a specific antibody.7 Therefore, it is crucial to now explore insoluble SOD1 in autopsied brains or biopsied cells (e.g. induced neurons from fibroblasts, olfactory neurons) from patients with recent-onset schizophrenia, and such future studies may utilize antibodies against insoluble forms of SOD1.8 A role of misfolded protein in schizophrenia has also been suggested by studies stemming from genetic susceptibility factors. Korth and associates9 reported the recruitment of Dysbindin protein to cell-invasive DISC1 aggresomes, suggesting the important convergence of two promising genetic risk factors and the significance of protein insolubility in cases of schizophrenia. The levels of CSF soluble SOD1 are not significantly different between chronic cases and matched healthy controls (data not shown). The possible contrast in SOD1 between recent-onset schizophrenia and chronic cases may be addressed in follow-up studies with larger sample size. It is possible that transient downregulation around the onset of schizophrenia might play an important pathophysiological role. Of note, some studies suggest that neuroleptic medication might increase plasma or serum SOD levels,10 although levels between peripheral blood and CSF are not necessarily correlated. In this report with one exception, all patients were on medication at the time of CSF acquisition. In summary, we report diminished CSF soluble SOD1 in cases of recent-onset schizophrenia and discuss this observation as supporting the previously proposed role of “oxidative stress” in the pathophysiology and onset of this disease. Increased oxidative stress can lead to synaptic deterioration and interneuron deficits relevant to the pathophysiology of schizophrenia. Furthermore, this observation may also be an entry point for other working hypotheses, such as those of SOD1 protein misfolding and aberrant control of proteolysis, which prompt further investigation.

Olfactory cells via nasal biopsy reflect the developing brain in gene expression profiles: Utility and limitation of the surrogate tissues in research for brain disorders

Human olfactory cells obtained by rapid nasal biopsy have been suggested to be a good surrogate system to address brain disease-associated molecular changes. Nonetheless, whether use of this experimental strategy is justified remains unclear. Here we compared expression profiles of olfactory cells systematically with those from the brain tissues and other cells. Principal component analysis indicated that the expression profiles of olfactory cells are very different from those of blood cells, but are closer to those of stem cells, in particular mesenchymal stem cells, that can be differentiated into the cells of the central nervous system.

Astroglial IFITM3 mediates neuronal impairments following neonatal immune challenge in mice

Interferon‐induced transmembrane protein 3 (IFITM3) ıplays a crucial role in the antiviral responses of Type I interferons (IFNs). The role of IFITM3 in the central nervous system (CNS) is, however, largely unknown, despite the fact that its expression is increased in the brains of patients with neurologic and neuropsychiatric diseases. Here, we show the role of IFITM3 in long‐lasting neuronal impairments in mice following polyriboinosinic‐polyribocytidylic acid (polyI:C, a synthetic double‐stranded RNA)‐induced immune challenge during the early stages of development. We found that the induction of IFITM3 expression in the brain of mice treated with polyI:C was observed only in astrocytes. Cultured astrocytes were activated by polyI:C treatment, leading to an increase in the mRNA levels of inflammatory cytokines as well as Ifitm3. When cultured neurons were treated with the conditioned medium of polyI:C‐treated astrocytes (polyI:C‐ACM), neurite development was impaired. These polyI:C‐ACM‐induced neurodevelopmental abnormalities were alleviated by ifitm3−/− astrocyte‐conditioned medium. Furthermore, decreases of MAP2 expression, spine density, and dendrite complexity in the frontal cortex as well as memory impairment were evident in polyI:C‐treated wild‐type mice, but such neuronal impairments were not observed in ifitm3−/− mice. We also found that IFITM3 proteins were localized to the early endosomes of astrocytes following polyI:C treatment and reduced endocytic activity. These findings suggest that the induction of IFITM3 expression in astrocytes by the activation of the innate immune system during the early stages of development has non‐cell autonomous effects that affect subsequent neurodevelopment, leading to neuropathological impairments and brain dysfunction, by impairing endocytosis in astrocytes. GLIA 2013

Cuprizone short-term exposure: astrocytic IL-6 activation and behavioral changes relevant to psychosis.

A growing body of evidence suggests the involvement of inflammatory processes in the pathophysiology of schizophrenia. Four- to 8-week exposure to cuprizone, a copper chelator, causes robust demyelination and has been used to build a model for multiple sclerosis. In contrast, we report here the effects of 1-week cuprizone exposure in mice. This short-term cuprizone exposure elicits behavioral changes that include augmented responsiveness to methamphetamine and phencyclidine, as well as impaired working memory. The cellular effects of 1-week cuprizone exposure differ substantially from the longer-term exposure; perturbation of astrocytes and microglia is induced without any sign of demyelination. Furthermore, the proinflammatory cytokine interleukin-6 was significantly up-regulated in glial fibrillary acidic protein (GFAP)-positive cells. We propose that this cuprizone short-term exposure may offer a model to study some aspects of biology relevant to schizophrenia and related conditions.

Altered MHC class I expression in dorsolateral prefrontal cortex of nonsmoker patients with schizophrenia

Schizophrenia (SZ) is a psychiatric disease with plausible neurodevelopmental etiology. Although genetic studies show significant association of immune molecules loci such as major histocompatibility complex (MHC) class I with SZ, it is not clear whether these immune molecules are involved in the pathology observed in SZ brains. MHC class I and the classical pathway components of complement system (C1q and C3) have been shown to regulate brain neuronal maturation and function. We have examined the expression of MHC class I and complement protein C3 in two frontal cortical regions of postmortem brains of SZ patients. Since cigarette smoking may modulate MHC class I protein expression and a higher rate of smoking is observed in SZ patients, we studied the expression of MHC class I and C3 in relation to the presence of smoking. We found that MHC class I protein expression is reduced in the dorsolateral prefrontal cortex (DLPFC) but not in the orbitofrontal cortex (OFC) of nonsmoker SZ patients. We did not observe SZ-associated changes in C3 mRNA expression. Our exploratory research suggests a potential involvement of MHC class I in SZ and implies that smoking might modulate its expression.

Mouse strain differences in phencyclidine-induced behavioural changes

Administration of phencyclidine (PCP) is acknowledged to generate a model of psychosis in animals. With the identification of genetic susceptibility factors for schizophrenia and bipolar disorder, great efforts have been made to generate genetic animal models for major mental illnesses. As these disorders are multifactorial, comparisons among drug-induced (non-genetic) and genetic models are becoming an important issue in biological psychiatry. A major barrier is that the standard mouse strain used in the generation of genetic models is C57BL/6, whereas almost all studies with PCP-induced models have utilized other strains. To fill this technical gap, we systematically compared the behavioural changes upon PCP administration in different mouse strains, including C57BL/6N, C57BL/6J, ddY, and ICR. We observed strain differences in PCP-induced hyperlocomotion and enhanced immobility in the forced swim test (ddY>>C57BL/6N and 6J>ICR). In contrast, there was no strain difference in the impairment of recognition memory in the novel object recognition memory test after withdrawal of chronic PCP administration. This study provides practical guidance for comparing genetic with PCP-induced models of psychosis in C57BL/6. Furthermore, such strain differences may provide a clue to the biological mechanisms underlying PCP-induced endophenotypes possibly relevant to major mental illnesses.

A novel balanced chromosomal translocation found in subjects with schizophrenia and schizotypal personality disorder: Altered L-serine level associated with disruption of PSAT1 gene expression

l-Serine is required for the synthesis of glycine and d-serine, both of which are NMDA receptor co-agonists. Although roles for d-serine and glycine have been suggested in schizophrenia, little is known about the role of the l-serine synthesizing cascade in schizophrenia or related psychiatric conditions. Here we report a patient with schizophrenia carrying a balanced chromosomal translocation with the breakpoints localized to 3q13.12 and 9q21.2. We examined this proband and her son with schizotypal personality disorder for chromosomal abnormalities, molecular expression profiles, and serum amino acids. Marked decrease of l-serine and glutamate was observed in the sera of the patient and her son, compared with those in normal controls. Interestingly, expression of PSAT1 gene, which is located next to the breakpoint and encodes one of the enzymes in the l-serine synthesizing cascade, was reduced in both patient and her son. Direct effect of impaired PSAT1 gene expression on decreased serum l-serine level was strongly implicated by rat astrocyte experiments. In summary, we propose an idea that PSAT1 may be implicated in altered serine metabolism and schizophrenia spectrum conditions.

A critical period of vulnerability to adolescent stress: epigenetic mediators in mesocortical dopaminergic neurons

The molecular basis of vulnerability to stress during the adolescent period is largely unknown. To identify potential molecular mediators that may play a role in stress-induced behavioral deficits, we imposed social isolation on a genetically vulnerable mouse model. We report that 3-week (5-8 weeks of age) adolescent stress in combination with disrupted-in-schizophrenia 1 (Disc1) genetic risk elicits alterations in DNA methylation of a specific set of genes, tyrosine hydroxylase, brain-derived neurotrophic factor and FK506 binding protein 5. The epigenetic changes in the mesocortical dopaminergic neurons were prevented when animals were treated with a glucocorticoid receptor (GR) antagonist RU486 during social isolation, which implicates the role for glucocorticoid signaling in this pathological event. We define the critical period of GR intervention as the first 1-week period during the stress regimen, suggesting that this particular week in adolescence may be a specific period of maturation and function of mesocortical dopaminergic neurons and their sensitivity to glucocorticoids. Our study may also imply the clinical significance of early detection and prophylactic intervention against conditions associated with adolescent social stress in individuals with genetic risk.