Summary Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental condition characterised by inattention, impulsivity and hyperactivity; it is frequently co-morbid with anxiety ...and conduct disorders, sleep perturbation and abnormal consummatory behaviours. Recent studies have implicated the neurosteroid-modulating enzyme steroid sulfatase (STS) as a modulator of ADHD-related endophenotypes. The effects of steroid sulfatase deficiency on homecage activity, feeding/drinking behaviours, anxiety-related behaviours (assayed in light-dark box and open field paradigms), social dominance and serum steroid hormone levels were determined by comparing 40,XY and 39,XY* O mice. Subsequently, mice administered the steroid sulfatase inhibitor COUMATE acutely were compared to vehicle-treated mice on behavioural tasks sensitive to enzyme deficiency to dissociate between its developmental and ongoing effects. 39,XY* O mice exhibited heightened reactivity to a novel environment, hyperactivity in the active phase, and increased water (but not food) consumption relative to 40,XY mice during a 24 h period; the former group also demonstrated evidence for heightened emotional reactivity. There was no difference in social dominance between the 40,XY and 39,XY* O mice. COUMATE administration had no effect on homecage activity, water consumption or anxiety measures in the open field. 39,XY* O mice exhibited significantly lower dehydroepiandrosterone (DHEA) serum levels than 40,XY mice, but equivalent corticosterone levels. Together with previous data, the present results suggest that steroid sulfatase may influence core and associated ADHD behavioural endophenotypes via both developmental and ongoing mechanisms, and that the 39,XY* O model may represent a useful tool for elucidating the neurobiological basis of these endophenotypes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
There is increasing awareness of the role genetic risk variants have in mediating vulnerability to psychiatric disorders such as schizophrenia and autism. Many of these risk variants encode synaptic ...proteins, influencing biological pathways of the postsynaptic density and, ultimately, synaptic plasticity. Fragile-X mental retardation 1 (FMR1) and cytoplasmic fragile-X mental retardation protein (FMRP)-interacting protein 1 (CYFIP1) contain 2 such examples of highly penetrant risk variants and encode synaptic proteins with shared functional significance. In this review, we discuss the biological actions of FMRP and CYFIP1, including their regulation of (i) protein synthesis and specifically FMRP targets, (ii) dendritic and spine morphology, and (iii) forms of synaptic plasticity such as long-term depression. We draw upon a range of preclinical studies that have used genetic dosage models of FMR1 and CYFIP1 to determine their biological function. In parallel, we discuss how clinical studies of fragile X syndrome or 15q11.2 deletion patients have informed our understanding of FMRP and CYFIP1, and highlight the latest psychiatric genomic findings that continue to implicate FMRP and CYFIP1. Lastly, we assess the current limitations in our understanding of FMRP and CYFIP1 biology and how they must be addressed before mechanism-led therapeutic strategies can be developed for psychiatric disorders.
Copy number variation (CNV) at chromosomal region 15q11.2 is linked to increased risk of neurodevelopmental disorders including autism and schizophrenia. A significant gene at this locus is ...cytoplasmic fragile X mental retardation protein (FMRP) interacting protein 1 (CYFIP1). CYFIP1 protein interacts with FMRP, whose monogenic absence causes fragile X syndrome (FXS). Fmrp knock-out has been shown to reduce tonic GABAergic inhibition by interacting with the δ-subunit of the GABAA receptor (GABAAR). Using in situ hybridization (ISH), qPCR, Western blotting techniques, and patch clamp electrophysiology in brain slices from a Cyfip1 haploinsufficient mouse, we examined δ-subunit mediated tonic inhibition in the dentate gyrus (DG). In wild-type (WT) mice, DG granule cells (DGGCs) responded to the δ-subunit-selective agonist THIP with significantly increased tonic currents. In heterozygous mice, no significant difference was observed in THIP-evoked currents in DGGCs. Phasic GABAergic inhibition in DGGC was also unaltered with no difference in properties of spontaneous IPSCs (sIPSCs). Additionally, we demonstrate that DG granule cell layer (GCL) parvalbumin-positive interneurons (PV+-INs) have functional δ-subunit-mediated tonic GABAergic currents which, unlike DGGC, are also modulated by the α1-selective drug zolpidem. Similar to DGGC, both IPSCs and THIP-evoked currents in PV+-INs were not different between Cyfip1 heterozygous and WT mice. Supporting our electrophysiological data, we found no significant change in hippocampal δ-subunit mRNA expression or protein level and no change in α1/α4-subunit mRNA expression. Thus, Cyfip1 haploinsufficiency, mimicking human 15q11.2 microdeletion syndrome, does not alter hippocampal phasic or tonic GABAergic inhibition, substantially differing from the Fmrp knock-out mouse model.
Copy number variation (CNV) at chromosomal region 15q11.2 is linked to increased risk of neurodevelopmental disorders including autism and schizophrenia. A significant gene at this locus is ...cytoplasmic fragile X mental retardation protein (FMRP) interacting protein 1 (
). CYFIP1 protein interacts with FMRP, whose monogenic absence causes fragile X syndrome (FXS).
knock-out has been shown to reduce tonic GABAergic inhibition by interacting with the δ-subunit of the GABA
receptor (GABA
R). Using
hybridization (ISH), qPCR, Western blotting techniques, and patch clamp electrophysiology in brain slices from a
haploinsufficient mouse, we examined δ-subunit mediated tonic inhibition in the dentate gyrus (DG). In wild-type (WT) mice, DG granule cells (DGGCs) responded to the δ-subunit-selective agonist THIP with significantly increased tonic currents. In heterozygous mice, no significant difference was observed in THIP-evoked currents in DGGCs. Phasic GABAergic inhibition in DGGC was also unaltered with no difference in properties of spontaneous IPSCs (sIPSCs). Additionally, we demonstrate that DG granule cell layer (GCL) parvalbumin-positive interneurons (PV
-INs) have functional δ-subunit-mediated tonic GABAergic currents which, unlike DGGC, are also modulated by the α
-selective drug zolpidem. Similar to DGGC, both IPSCs and THIP-evoked currents in PV
-INs were not different between
heterozygous and WT mice. Supporting our electrophysiological data, we found no significant change in hippocampal δ-subunit mRNA expression or protein level and no change in α
/α
-subunit mRNA expression. Thus,
haploinsufficiency, mimicking human 15q11.2 microdeletion syndrome, does not alter hippocampal phasic or tonic GABAergic inhibition, substantially differing from the
knock-out mouse model.
The 39,XY*O mouse, which lacks the orthologues of the ADHD and autism candidate genes STS (steroid sulphatase) and ASMT (acetylserotonin O-methyltransferase), exhibits behavioural phenotypes relevant ...to developmental disorders. The neurobiology underlying these phenotypes is unclear, although there is evidence for serotonergic abnormalities in the striatum and hippocampus.
Using microarray and quantitative gene expression analyses, and gas chromatography-mass spectrometry, we compared brain gene expression and steroid biochemistry in wildtype (40,XY) and 39,XY*O adult mice to identify non-obvious genetic and endocrine candidates for between-group differences in behaviour and neurochemistry. We also tested whether acute STS inhibition by COUMATE in wildtype (40,XY) adult male mice recapitulated any significant gene expression or biochemical findings from the genetic comparison. Data were analysed by unpaired t-test or Mann Whitney U-test depending on normality, with a single factor of KARYOTYPE.
Microarray analysis indicated seven robust gene expression differences between the two groups (Vmn2r86, Sfi1, Pisd-ps1, Tagap1, C1qc, Metap1d, Erdr1); Erdr1 and C1qc expression was significantly reduced in the 39,XY*O striatum and hippocampus, whilst the expression of Dhcr7 (encoding 7-dehydrocholesterol reductase, a modulator of serotonin system development), was only reduced in the 39,XY*O hippocampus. None of the confirmed gene expression changes could be recapitulated by COUMATE administration. We detected ten free, and two sulphated steroids in 40,XY and 39,XY*O brain; surprisingly, the concentrations of all of these were equivalent between groups.
Our data demonstrate that the mutation in 39,XY*O mice: i) directly disrupts expression of the adjacent Erdr1 gene, ii) induces a remarkably limited suite of downstream gene expression changes developmentally, with several of relevance to associated neurobehavioural phenotypes and iii) does not elicit large changes in brain steroid biochemistry. It is possible that individuals with STS/ASMT deficiency exhibit a similarly specific pattern of gene expression changes to the 39,XY*O mouse, and that these contribute towards their abnormal neurobiology. Future work may focus on whether complement pathway function, mitochondrial metabolism and cholesterol biosynthesis pathways are perturbed in such subjects.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In addition to their established role in nervous system development, vitamin A and related retinoids are emerging as regulators of adult brain function. Accutane (13-cis-retinoic acid, isotretinoin) ...treatment has been reported to increase depression in humans. Recently, we showed that chronic administration of 13-cis-retinoic acid (13-cis-RA) to adolescent male mice increased depression-related behaviors. Here, we have examined whether 13-cis-RA regulates components involved in serotonergic neurotransmission in vitro. We used the RN46A-B14 cell line, derived from rat embryonic raphe nuclei. This cell line synthesizes serotonin (5-hydroxytryptamine, 5-HT) and expresses the 5-HT(1A) receptor and the serotonin reuptake transporter (SERT). Cells were treated with 0, 2.5, or 10 microM 13-cis-RA for 48 or 96 hrs, and the levels of 5-HT; its metabolite, 5-hydroxyindoleacetic acid (5HIAA); 5-HT(1A) receptor; and SERT were determined. Treatment with 13-cis-RA for 96 hrs increased the intracellular levels of 5-HT and tended to increase intra-cellular 5HIAA levels. Furthermore, 48 hrs of treatment with 2.5 and 10 microM 13-cis-RA significantly increased 5-HT(1A) protein to 168.5 +/- 20.0% and 148.7 +/- 2.2% of control respectively. SERT protein levels were significantly increased to 142.5 +/- 11.1% and 119.2 +/- 3.6% of control by 48 hrs of treatment with 2.5 and 10 microM of 13-cis-RA respectively. Increases in both 5-HT(1A) receptor and SERT proteins may lead to decreased serotonin availability at synapses. Such an effect of 13-cis-RA could contribute to the increased depression-related behaviors we have shown in mice.
Alterations in synaptic signaling and plasticity occur during the refinement of neural circuits over the course of development and the adult processes of learning and memory. Synaptic plasticity ...requires the rearrangement of protein complexes in the postsynaptic density (PSD), trafficking of receptors and ion channels and the synthesis of new proteins. Activity-induced short Homer proteins, Homer1a and Ania-3, are recruited to active excitatory synapses, where they act as dominant negative regulators of constitutively expressed, longer Homer isoforms. The expression of Homer1a and Ania-3 initiates critical processes of PSD remodeling, the modulation of glutamate receptor-mediated functions, and the regulation of calcium signaling. Together, available data support the view that Homer1a and Ania-3 are responsible for the selective, transient destabilization of postsynaptic signaling complexes to facilitate plasticity of the excitatory synapse. The interruption of activity-dependent Homer proteins disrupts disease-relevant processes and leads to memory impairments, reflecting their likely contribution to neurological disorders.
Abstract Retinoids, vitamin A related compounds, have an established role in the development of the nervous system and are increasingly recognized to play a role in adult brain function. The ...synthetic retinoid, 13-c is -retinoic acid (13- cis -RA, Roaccutane) is widely used to treat severe acne but has been linked to an increased risk of neuropsychiatric side effects, including depression. Here we report that chronic administration with 13- cis -RA (1 mg/kg i.p. daily, 7–14 days) in adult rats reduced aggression- and increased flight-related behaviours in the resident–intruder paradigm. However, in the forced swim, sucrose consumption and open field tests treatment for up to 6 weeks with 13- cis -RA did not modify behaviour in adult or juvenile animals. The behavioural change observed in the resident–intruder paradigm is directly opposite to that observed with chronic antidepressant administration. These findings indicate that when a suitably sensitive behavioural test is employed then chronic administration of 13- cis -RA in adult rats induces behavioural changes consistent with a pro-depressant action.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Vitamin A and its derivatives, known as retinoids, are involved in a number of functions in the developing and adult brain (Lane et al., 2005). Roaccutane (13-cis-retinoic acid, 13-cis-RA) is a ...synthetic retinoid used for the treatment of severe cystic acne, although its use has been controversially associated with adverse psychiatric events including depression. In this thesis, the presence of retinoid receptors in the rat hippocampus was verified and a similar profile of expression was observed in the rat raphe nuclei for the first time. The expression of retinoid receptors in brain regions that are implicitly associated with depression pathology provides proof of concept for retinoids to influence depressive behaviour. The ability of 13-cis-RA treatment to induce a pro-depressive profile in animal models of depression-related behaviour was tested. In the resident-intruder paradigm, adult rats treated for 7 or 14 days with 13-cis-RA (1mg/kg, i.p.) showed reduced aggressive behaviour, with a concomitant increase in flight submit and flight escape behaviours, compared with vehicle-treated controls. These findings are indicative of increased depression-related behaviour. However, chronic treatment did not alter depression-related behaviour in the forced swim test and sucrose consumption anhedonia paradigms The molecular mechanisms mediating 13-cis-RA-induced depression were investigated by examining monoaminergic gene expression, protein levels and neurotransmitter levels in rat brain tissue and plasma and an in vitro model. The majority of serotonergic components (SERT, 5-HT1AR, 5-HT1BR and MAOA) were not altered by chronic 13-cis-RA treatment, with the possible exception of TPH2 gene/protein expression and increased 5-HT levels in platelets. In fact, the expression of D2 dopamine receptor was significantly elevated in the RN46A-B14 cell line (10μM 13-cis-RA, 48 h) and was similarly elevated at the protein level in the juvenile rat hippocampus (1mg/kg/day, i.p., 6 weeks), suggesting dopaminergic pathways may be of importance. There was also a trend in the data to suggest that 13-cis-RA-treated juvenile rats may be more susceptible the molecular alterations than corresponding adult rats. xii
A neem-based insecticide, Neemix 4.5, was applied to forest pond enclosures at environmentally realistic concentrations (i.e., below the worst-case expected environmental concentration of 35μgL−1). ...Crustacean zooplankton communities were examined by multivariate ordination (nonmetric multidimensional scaling) and time-course analyses of population trends among indicator taxa over two field seasons to determine application effects on community structure and recovery patterns. Significant effects on zooplankton community structure were detected at all main test concentrations (n=5) of 28, 17, and 10μgL−1 azadirachtin. There was also evidence of adverse effects on zooplankton communities at an auxiliary test concentration (n=2) of 5μgL−1 azadirachtin. Community-level effects resulted primarily from reductions in adult copepods with short-term, reciprocal increases in cladocerans. Copepod nauplii were not significantly affected. Response patterns suggested that the reductions in adult copepods resulted from growth-regulating effects of the active ingredient azadirachtin, or other neem compounds, and not from formulation ingredients. There was no evidence of recovery among adult copepods within the season of application. At the beginning of the second sampling season, there were apparent carryover effects similar to the community responses in the previous year. By the end of the second season, there was evidence indicating recovery of community structure at the two lower test concentrations of 10 and 17μgL−1, but not at 28μgL−1. The selective toxicity to adult copepods is problematic in that this group has a relatively long life cycle (1 year), contributes a major component of zooplankton biomass and respiration, and occupies critical functional guilds within zooplankton food web structures. Mitigation measures such as reductions in application rates and efforts to avoid deposition of sprayed materials on water bodies will be required to reduce the risk of harmful effects on zooplankton communities of forest ponds and other shallow, standing-water bodies.
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