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Sotos syndrome is a developmental disorder characterized by a suite of clinical features. In children, the three cardinal features of Sotos syndrome are a characteristic facial appearance, learning disability and overgrowth (height and/or head circumference > 2 SDs above average). These features are also evident in adults with this syndrome. Over 90% of Sotos syndrome patients are haploinsufficient for the gene encoding nuclear receptor-binding Su(var)3-9, Enhancer-of-zesteand Trithorax domain-containing protein 1 (NSD1). NSD1 is a histone methyltransferase that catalyzes the methylation of lysine residue 36 on histone H3. However, although the symptomology of Sotos syndrome is well established, many aspects of NSD1 biology remain unknown. Here, we assessed the expression of Nsd1 within the mouse brain, and showed a predominantly neuronal pattern of expression for this histone-modifying factor. We also generated a mouse strain lacking one allele of Nsd1 and analyzed morphological and behavioral characteristics in these mice, showing behavioral characteristics reminiscent of some of the deficits seen in Sotos syndrome patients.

Background Type 1 adult hippocampal neural stem cells (AH-NSCs) continue to generate neurons throughout life, albeit at a very low rate. The relative quiescence of this population of cells has led to many studies investigating factors that may increase their division. Current methods of identifying dividing AH-NSCs in vivo require the identification and tracing of radial processes back to nuclei within the subgranular zone. However, caveats to this approach include the time-intensive nature of identifying AH-NSCs with such a process, as well as the fact that this approach ignores the relatively more active population of horizontally oriented AH-NSCs that also reside in the subgranular zone. Results Here, we describe, and then verify using Hes5::GFP mice, that labelling for the cell-cycle marker Ki67, and selection against the intermediate progenitor cell marker TBR2 (Ki67+ve; TBR2–ve nuclei) is sufficient to identify dividing horizontally- and radially-orientated AH-NSCs in the adult mouse hippocampus. Conclusion These findings provide a simple and accurate way to quantify dividing AH-NSCs in vivo using a morphology independent approach that will facilitate studies into neurogenesis within the hippocampal stem cell niche of the adult brain. This article is protected by copyright. All rights reserved.

Background Epidemiological evidence suggests that developmental vitamin D (DVD) deficiency is a risk factor for neuropsychiatric disorders, such as schizophrenia. DVD deficiency in rats is associated with altered brain structure and adult behaviours indicating alterations in dopamine and glutamate signalling. Developmental alterations in dopamine neurotransmission have also been observed in DVD-deficient rats but a comprehensive assessment of brain neurochemistry has not been undertaken. Thus, the current study determined the regional concentrations of dopamine, noradrenaline, serotonin, glutamine, glutamate and γ-aminobutyric acid (GABA), and associated metabolites, in DVD-deficient neonates. Methods Sprague-Dawley rats were fed a vitamin D deficient diet or control diet six weeks prior to mating until birth and housed under UVB-free lighting conditions. Neurotransmitter concentration was assessed by high-performance liquid chromatography on post-mortem neonatal brain tissue. Results Ubiquitous reductions in the levels of glutamine (12–24%) were observed in DVD-deficient neonates compared with control neonates. Similarly, in multiple brain regions DVD-deficient neonates had increased levels of noradrenaline and serine compared with control neonates. In contrast, increased levels of dopamine and decreased levels of serotonin in DVD-deficient neonates were limited to striatal subregions compared with controls. Conclusions Our results confirm that DVD deficiency leads to changes in multiple neurotransmitter systems in the neonate brain. Importantly, this regionally-based assessment in DVD-deficient neonates identified both widespread neurotransmitter changes (glutamine/noradrenaline) and regionally selective neurotransmitter changes (dopamine/serotonin). Thus, vitamin D may have both general and local actions depending on the neurotransmitter system being investigated. Taken together, these data suggest that DVD deficiency alters neurotransmitter systems relevant to schizophrenia in the developing rat brain.

Advanced paternal age (APA) is associated with an increased risk of adverse health outcomes in offspring, including autism and schizophrenia. In the present study, we investigated the behaviour of young (3-month-old; Control), middle aged (12 to 15-month-old; APA1) and old (24-month-old; APA2) C57BL/6J sires and their adult offspring. Male and female mice were tested at 10 weeks of age on a behavioural test battery including the elevated plus-maze, hole board, light/dark emergence, forced swim test, novelty-suppressed feeding and for prepulse inhibition of the acoustic startle response. Increasing the APA sire age to 24 months was shown to be associated with increased anxiety-related behaviour in the offspring, and indicated that increasing APA sire age produced a more robust hypoexplorative phenotype. Thus, increasing paternal age was associated with an increase in severity of an anxiogenic phenotype in their adult offspring. Ultimately, the results of these studies show that mouse models of APA are valuable for elucidating the mechanisms by which APA influences brain-related outcomes.

Evidence suggests that low concentrations of 25-hydroxyvitamin D(3) (25OHD3) during gestation may be associated with a range of adverse health outcomes in later life. Retrospective estimation of perinatal vitamin D status using questionnaires is extremely unreliable and stored serum samples are rarely available. We aimed to validate the use of dried blood spots (DBS) to estimate perinatal vitamin D status and to determine whether inter-group differences in cord serum 25OHD3 are reflected in DBS. We examined 25OHD3 in 4-year-old frozen cord sera and matched DBS from neonates born at a hospital in Melbourne, Australia (n = 100). We examined the correlation between these values and also investigated whether the expected seasonal (winter/spring vs. summer/autumn) difference in serum 25OHD3 was reflected in DBS values. 25OHD3 was assayed in triplicate using tandem mass spectroscopy in both a 3 microL sample of cord serum and in matched 3 mm punches from archived DBS. 25OHD3 concentrations in neonatal cord serum and DBS were highly correlated (r = 0.85, P < 0.0001). As expected, serum 25OHD3 concentrations were higher in neonates born in summer/autumn (December to March) vs. winter/spring (April to November) (median 46.6 vs. 23.7 nmol/L, P < 0.0001). A comparable difference was seen in DBS values (17.8 vs. 10.5 nmol/L, P = 0.0001). Archived DBS samples provided a valid measure of perinatal vitamin D status and identified inter-seasonal differences in perinatal 25OHD3 concentrations. They could be used for case-control studies investigating the association between perinatal vitamin D status and later health outcomes.

Although changes to neural circuitry are believed to underlie behavioural characteristics mediated by the hippocampus, the contribution of neurogenesis to this process remains controversial. This is partially because the molecular regulators of neurogenesis remain to be fully elucidated, and experiments generically preventing neurogenesis have, for the most part, depended on paradigms involving irradiation. Here we show that mice lacking the p75 neurotrophin receptor (p75(NTR-/-)) have 25% fewer neuroblasts and 50% fewer newborn neurons in the dentate gyrus, coincident with increased rates of cell death of newly born cells and a significantly smaller granular cell layer and dentate gyrus, than those of p75(NTR+/+) mice. Whereas p75(NTR-/-) mice had increased latency to feed in a novelty-suppressed feeding paradigm they had increased mobility in another test of "depression", the tail-suspension test. p75(NTR-/-) mice also had subtle behavioural impairment in Morris water maze tasks compared to wild-type animals. No difference between genotypes was found in relation to anxiety or exploration behaviour based on the elevated-plus maze, light-dark, hole-board, T-maze or forced-swim tests. Overall, this study demonstrates that p75(NTR) is an important regulator of hippocampal neurogenesis, with concomitant effects on associated behaviours. However, the behavioural attributes of the p75(NTR-/-) mice may be better explained by altered circuitry driven by the loss of p75(NTR) in the basal forebrain, rather than direct changes to neurogenesis.

The acidity constant of protonated 2-[bis(2-hydroxyethyl)amino]-2(hydroxymethyl)-1,3-propanediol (Bistris) has been measured. The influence of hydroxo groups on the basicity of Bistris and related bases is discussed. The interaction of Bistris with the metal ions (M2+) Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+, and Pb2+ was studied by potentiometry and spectrophotometry in aqueous solution (I = 1.0 M, KNO3; 25 degrees C) and the stability constants of the M(Bistris)2+ complexes were determined. Unexpectedly Ca(Bistris)2+ is the most stable among the alkaline earth ion complexes (log KCaCa(Bistris) = 2.25; the corresponding values for the Mg2+, Sr2+ and Ba2+ complexes are 0.34, 1.44 and 0.85, respectively). The ions of the 3d series follow the Irving-Williams sequence: log KMnMn(Bistris) = 0.70, for Cu2+, 5.27 and Zn2+ 2.38. Ternary complexes containing ATP4- as a second ligand were also investigated: the values for delta log KM (= log KM(ATP)M(ATP)(Bistris) -log KMM(Bistris) are in general negative (e.g. delta log KCa = -0.40 or delta log KCu = -1.65), thus indicating that the interaction of Bistris with M(ATP)2- is somewhat less pronounced tan with M2+. However, even in mixed-ligand systems, complex formation may still be considerable, hence great reservations should be exercised in employing Bistris as a buffer in systems containing metal ions. Moreover, in several cases delta log KM is relatively high [for Mg2+-ATP4- -Bistris even positive], indicating some cooperativity between the coordinated ligands, possibly hydrogen-bond formation. Distributions of the complexes in dependence on pH are given, and the structures of the binary M(Bistris)2+ and the ternary M(ATP) (Bistris)2- complexes are discussed. The participation of Bistris hydroxo groups in complex formation is evident.

Intramuscular injection of the naturally occurring prostaglandin F-2alpha (PGF(2alpha)) to sexually mature female pigs induces luteolysis and rapidly elicits a behavioural response consistent with pre-partum nest-building. Intramuscular injection of the synthetic prostaglandin F-2alpha (cloprostenol) also induces luteolysis but no nest-building behaviour is observed. The effects of PGF(2alpha), but not cloprostenol, on nest-building behaviour may be mediated via peripheral PGF(2alpha) receptors (FP) or via direct action on central FP receptors. We have previously shown FP receptor mRNA to be localized in porcine paraventricular nucleus (PVN), supraoptic nucleus (SON) and pars dorso-medialis of the suproptic nucleus (SOD), suprachiasmatic nucleus, choroid plexus and anterior and intermediate pituitary lobes. In this experiment, we examined hypothalamic expression of the immediate early genes c-fos and c-jun mRNA after treatment with PGF(2alpha) or cloprostenol. Twenty-one 8-month-old nulliparous female pigs (gilts) were injected intramuscularly with a luteolytic dose of PGF(2alpha) (15 mg), cloprostenol (175 mug) or saline control, their behaviour was recorded and they were killed 60 min later. Coronal hypothalamic sections and control ovarian tissues were incubated with 45-mer oligonucleotide probes complementary to porcine c-fos and c-jun genes using standard in situ hybridization histochemistry techniques. Significantly higher c-fos and c-jun mRNA expression was found in PGF(2alpha)-treated compared to saline or cloprostenol-treated pigs in the PVN, SON and SOD. Significantly higher c-fos and c-jun mRNA expression was found in corpus lutea of PGF(2alpha) and cloprostenol-treated pigs compared to saline controls. Treatment with PGF(2alpha) induced nest-building behaviour whereas treatment with cloprostenol and saline did not. This suggests that PGF(2alpha), or one of its metabolites, and not cloprostenol, crosses the blood-brain barrier and acts directly on hypothalamic receptors to mediate its effect on nest-building behaviour.