Florey Department of Neuroscience and Mental Health - Research Publications

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2013 - 2014 3
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Type: Journal Article × Subject: Schizophrenia × Author: van den Buuse, Maarten ×

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    Modafinil disrupts prepulse inhibition in mice: Strain differences and involvement of dopaminergic and serotonergic activation
    Kwek, P ; van den Buuse, M (ELSEVIER SCIENCE BV, 2013-01-15)
    Modafinil is a wakefulness-promoting agent with possible beneficial effects for the management of addiction and in psychiatric conditions, but also with abuse potential of its own. The mechanism of action of modafinil remains unclear. We studied pharmacological mechanisms in the effect of modafinil on prepulse inhibition (PPI), a model of sensorimotor gating. Mice were tested in automated startle boxes after administration of modafinil and antagonist drugs. Oral administration of 100mg/kg of modafinil, but not lower doses, caused a significant reduction of PPI in C57Bl/6 mice, but not Balb/c mice. This effect of modafinil could be blocked by co-treatment with the dopamine D(2) receptor antagonist, haloperidol, and the serotonin (5-HT) 2A receptor antagonist, ketanserin, but not the 5-HT(1A) receptor antagonist, WAY100,635. At 30mg/kg, which did not influence PPI, modafinil inhibited PPI disruption caused by the dopamine transporter inhibitor, GBR12909. There was no interaction between modafinil and the serotonin transporter inhibitor, fluoxetine. There were no consistent effects of modafinil on startle amplitude. These results show that oral modafinil treatment may cause disruption of PPI in mice. This effect was strain-dependent, involving dopamine D(2) and 5-HT(2A) receptor activation, and was likely mediated by an interaction with the dopamine transporter. These results extend our insight into the behavioral effects of modafinil and could be of importance for the clinical use of this agent as they may indicate an increased risk of side-effects in conditions where PPI is already reduced, such as in schizophrenia and bipolar disorder.
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    Sex differences in the adolescent developmental trajectory of parvalbumin interneurons in the hippocampus: A role for estradiol
    Wu, YC ; Du, X ; van den Buuse, M ; Hill, RA (PERGAMON-ELSEVIER SCIENCE LTD, 2014-07)
    OBJECTIVE: Gender differences in the neurodevelopmental disorder, schizophrenia, have been described for nearly all features of the illness. Reduced hippocampal expression of the GABAergic interneuron marker, parvalbumin (PV), and GABA synthesizing enzyme, GAD67, are consistently reported in schizophrenia. However, little is known of the expression patterns of hippocampal PV and GAD67 during adolescence and their interaction with sex steroid hormones during adolescent development. This study examined the effects of altered sex steroid hormone levels during adolescence on protein levels of PV, GAD67 and estrogen receptors (ERα/β) in the hippocampus of mice. METHODS: Protein expression of PV and GAD67 was measured in the dorsal (DHP) and ventral (VHP) hippocampus of female and male C57Bl/6 mice by Western blot in a week by week analysis from pre-pubescence to adulthood (week 3-12). Fluorescent immunohistochemistry (IHC) was used to investigate the relationship between ERs and PV(+) cells in the hippocampus of female mice at young adulthood (week 10-11). To further examine the role of sex steroid hormones on PV and GAD67 expression, gonadectomy and hormone replacement was done at 5 weeks of age. RESULTS: Female mice showed a significant gradual increase in PV expression from 3 to 12 weeks of age in the DHP and VHP which correlated with serum 17β-estradiol levels. Fluorescent IHC showed approximately 30-50% co-localization of ER-α in PV(+) cells in the female DHP and VHP (dentate gryus/hilus and CA1-CA3). Adolescent ovariectomy significantly reduced PV expression in the DHP but not VHP of female mice, while 17β-estradiol replacement prevented this deficit in DHP PV levels. ER-α expression, but not ER-β, was also reduced in the DHP following ovariectomy with no significant effect of 17β-estradiol replacement. In contrast to female mice, male mice did not show any significant changes in hippocampal PV/GAD67 expression throughout adolescent development. Furthermore, adolescent castration and treatment with testosterone or dihydrotestosterone produced no changes in PV/GAD67 expression. CONCLUSIONS: Our data suggest a differential developmental trajectory of PV expression between the sexes and manipulating circulating levels of sex steroid hormones by ovariectomy alters this trajectory in a region-dependent manner. This may be mediated via ER-α signaling as this receptor was found to be co-localized with PV(+) cells in the female mouse hippocampus. Alternative mechanisms of 17β-estradiol-induced regulation of PV expression are also discussed herein. Together, results from the present study may offer more insight into neurodevelopmental disorders, including schizophrenia, where sex steroid hormones and GABAergic markers are implicated in the pathophysiology of the illness.
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    Sex-dependent alterations in BDNF-TrkB signaling in the hippocampus of reelin heterozygous mice: a role for sex steroid hormones
    Hill, RA ; Wu, Y-WC ; Gogos, A ; van den Buuse, M (WILEY, 2013-08)
    Neurodevelopmental psychiatric disorders such as schizophrenia may be caused by a combination of gene × environment, gene × gene, and/or gene × sex interactions. Reduced expression of both Reelin and Brain-Derived Neurotrophic factor (BDNF) has been associated with schizophrenia in human post-mortem studies. However, it remains unclear how Reelin and BDNF interact (gene × gene) and whether this is sex-specific (gene × sex). This study investigated BDNF-TrkB signaling in the hippocampus of male and female Reelin heterozygous (Rln(+/-) ) mice. We found significantly increased levels of BDNF in the ventral hippocampus (VHP) of female, but not male Rln(+/-) compared to wild-type (WT) controls. While levels of TrkB were not significantly altered, phosphorylated TrkB (pTrkB) levels were significantly lower, again only in female Rln(+/-) compared to WT. This translated to downstream effects with a significant decrease in phosphorylated ERK1 (pERK1). No changes in BDNF, TrkB, pTrkB or pERK1/2 were observed in the dorsal hippocampus of Rln(+/-) mice. Ovariectomy (OVX) had no effect in WT controls, but caused a significant decrease in BDNF expression in the VHP of Rln(+/-) mice to the levels of intact WT controls. The high expression of BDNF was restored in OVX Rln(+/-) mice by 17β-estradiol treatment, suggesting that Rln(+/-) mice respond differently to an altered estradiol state than WT controls. In addition, while OVX had no significant effect on TrkB or ERK expression/phosphorylation, OVX + estradiol treatment markedly increased TrkB and ERK1 phosphorylation in Rln(+/-) and, to a lesser extent in WT controls, compared to intact genotype-matched controls. These data may provide a better understanding of the interaction of Reelin and BDNF in the hippocampus, which may be involved in schizophrenia.