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Vitamin D deficiency is prevalent in adults and is associated with cognitive impairment. However, the mechanism by which adult vitamin D (AVD) deficiency affects cognitive function remains unclear. We examined spatial memory impairment in AVD-deficient BALB/c mice and its underlying mechanism by measuring spine density, long term potentiation (LTP), nitric oxide (NO), neuronal nitric oxide synthase (nNOS), and endothelial NOS (eNOS) in the hippocampus. Adult male BALB/c mice were fed a control or vitamin D deficient diet for 20 weeks. Spatial memory performance was measured using an active place avoidance (APA) task, where AVD-deficient mice had reduced latency entering the shock zone compared to controls. We characterised hippocampal spine morphology in the CA1 and dentate gyrus (DG) and made electrophysiological recordings in the hippocampus of behaviourally naïve mice to measure LTP. We next measured NO, as well as glutathione, lipid peroxidation and oxidation of protein products and quantified hippocampal immunoreactivity for nNOS and eNOS. Spine morphology analysis revealed a significant reduction in the number of mushroom spines in the CA1 dendrites but not in the DG. There was no effect of diet on LTP. However, hippocampal NO levels were depleted whereas other oxidation markers were unaltered by AVD deficiency. We also showed a reduced nNOS, but not eNOS, immunoreactivity. Finally, vitamin D supplementation for 10 weeks to AVD-deficient mice restored nNOS immunoreactivity to that seen in in control mice. Our results suggest that lower levels of NO and reduced nNOS immunostaining contribute to hippocampal-dependent spatial learning deficits in AVD-deficient mice.

Contains fulltext : 218305.pdf (Publisher’s version ) (Closed access) BACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative. METHODS: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology. RESULTS: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor beta signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory. CONCLUSIONS: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor beta signaling and hippocampal function.

Developmental vitamin D (DVD) deficiency is a risk factor for schizophrenia. In rodents we show that DVD-deficiency alters brain development and produces behavioral phenotypes in the offspring of relevance to the positive symptoms of schizophrenia. The aims of this study are to examine behavioral phenotypes specific to the cognitive and negative symptoms of schizophrenia in this model, and to vary the duration of vitamin D deficiency during gestation and beyond birth. We hypothesize that a longer duration of DVD-deficiency would result in greater behavioral impairments. Female vitamin D-deficient Sprague Dawley dams were mated at 10 weeks of age. Dietary vitamin D was reintroduced to dams and/or pups at different developmental time-points: Conception, Birth, Post-natal day (PND) 6 and PND21. Adult male and female offspring were assessed on a battery of behavioral tests, including sucrose preference, open field, novel object recognition (NOR), social approach and social novelty. We find that all windows of DVD-deficiency impaired NOR a cognitive measure that requires intact recognition memory. Sucrose consumption, social approach and social memory negative symptom-like phenotypes were unaffected by any maternal dietary manipulation. In addition, contrary to our hypothesis, we find that rats in the Conception group, that is the shortest duration of vitamin D deficiency, demonstrate increased locomotor activity, and decreased interaction time with novel objects. These findings have implications for the increasing number of studies examining the preclinical consequences of maternal vitamin D deficiency, and continue to suggest that adequate levels of maternal vitamin D are required for normal brain development.

It is well established that vitamin D is essential in calcium homeostasis and bone metabolism. Recent evidence has exposed further roles of vitamin D in adult brain function, specifically indicating that low vitamin D levels during adulthood may be related to cognitive impairment. We have recently shown that adult vitamin D (AVD) deficiency disrupts hippocampal-dependent learning and structural brain connectivity in BALB/c mice. The BALB/c mouse strain is more vulnerable to social stress compared with other resilient mouse strains, such as C57BL/6J mice. Therefore, the primary aim of this research was to examine C57BL/6J mice exposed to varying levels of vitamin D (0, 1500 and 15,000 IU/vitamin D3/kg referred to as deficient, control and elevated, respectively) for 10 weeks. The mice were assessed for hippocampal-dependent learning using the active place avoidance (APA) task. Mice were tested for behaviours that could alter performance on the APA task, and hippocampal tissue was analysed for catecholamine and protein expression. Vitamin D status did not affect spatial learning and memory, general behavioural domains, or catecholamine or protein expression in C57BL/6J mice. Overall, these results indicate that, in contrast to BALB/c mice, vitamin D status does not impact on hippocampal-dependent behaviour in young and healthy, adult male C57BL/6J mice.

Behavioural sensitization is a putative mechanism in the pathophysiology of drug addiction and neuropsychiatric disorders such as schizophrenia. In rodents, drug-induced behavioural sensitization has been described for several different drug classes. The N-methyl-D-aspartate receptor antagonist MK-801 can inhibit sensitization to other drugs of abuse. However, MK-801 also produces behavioural sensitization to its own hyperlocomotor inducing effects, suggesting that MK-801 sensitization has a distinctive mechanism of action. The aim of this study was to carry out a functional and molecular analysis of the nucleus accumbens (NAc) of adult male Sprague-Dawley rats sensitized to MK-801 (seven daily injections of 0.25 mg/kg, 5 days of withdrawal and subsequent 0.25 mg/kg challenge), or following acute MK-801 (0.25 mg/kg), or naive rats as controls. Locomotor activity was the primary measure of sensitization. Ex-vivo slice electrophysiology showed a decrease in the excitatory synaptic strength in the NAc of rats sensitized to MK-801 compared with acute MK-801 treatment or naive controls. An LC-MS/MS SWATH proteomics approach showed that proteins altered by MK-801 sensitization were predominantly related to functions including calcium and glutamate signalling, and mitochondrial dysfunction. These results shed some light on neural changes in the NAc after sensitization to MK-801. This model could prove useful for studying the role of N-methyl-D-aspartate receptors in the pathophysiology of drug addiction and schizophrenia.

Repeated exposure to psychostimulants that either increase dopamine (DA) release or target N-methyl-d-aspartate (NMDA) receptors can induce behavioural sensitisation, a phenomenon that may be important for the processes of addiction and even psychosis. A critical component of behavioural sensitisation is an increase in DA release within mesocorticolimbic circuits. In particular, sensitisation to amphetamine leads to increased DA release within well-known sub-cortical brain regions and also regulatory regions such as prefrontal cortex (PFC). However, it is unknown how DA release within the PFC of animals is altered by sensitisation to NMDA receptor antagonists. The aims of the present study were twofold, firstly to examine whether a single dose of dizocilpine maleate (MK-801) could induce long-term behavioural sensitisation and secondly to examine DA release in the PFC of sensitised rats. Behavioural sensitisation was assessed by measuring locomotion after drug exposure. DA release in the PFC was measured using freely moving microdialysis. We show that a single dose of MK-801 can induce sensitisation to subsequent MK-801 exposure in a high percentage of rats (66 %). Furthermore, rats sensitised to MK-801 have altered DA release and turnover in the PFC compared with non-sensitised rats. Schizophrenia patients have been postulated to have ‘endogenous sensitisation’ to psychostimulants. MK-801-induced sensitised rats, in particular when compared with non-sensitised rats, provide a useful model for studying PFC dysfunction in schizophrenia.

Different patterns of bone marrow (BM) infiltration by diffuse large B cell lymphomas (DLBCL) have been described. A pure nodular pattern is uncommon, and the pathologic features, as well as the clinical correlates of DLBCL manifesting this pattern in the BM have not been well characterized. We evaluated BM biopsies involved by large B cell lymphomas diagnosed at our institute over an 11-year period to assess the morphology, phenotype, cytogenetic abnormalities, and clinical features of cases associated with a nodular pattern. A distinct nodular pattern of BM involvement was noted in 14 out of 55 (25%) cases. Although both EBV+ and EBV− DLBCL with this pattern were identified, a pure nodular pattern was significantly more common in EBV+ DLBCL compared to EBV− DLBCL (8/9, 89% versus 6/46, 13%; P = 0.00002). The majority of EBV+ DLBCL associated with a nodular pattern had distinctive morphologic features (polymorphic cellular infiltrate and pleomorphic cytology), and CD30 expression was more commonly observed in this group (P = 0.0163). All EBV+ DLBCL and two out of six (33%) EBV− DLBCL had nongerminal center phenotypes. No recurrent cytogenetic abnormalities were detected in either group. Importantly, all EBV+ DLBCL occurred in individuals with immune dysfunction (organ transplant recipients, HIV infection) or in those >50 years of age. Our study indicates a much higher predilection for EBV+ DLBCL to involve the marrow in a nodular pattern compared to EBV− cases and highlights similarities in the morphologic pattern of BM involvement by previously recognized subsets of immunodeficiency-related EBV + lymphomas and the newer entity of “EBV+ DLBCL of the elderly.”

It is now widely acknowledged that exposure to adverse environmental factors in utero may not only affect how the brain develops but have long-lasting consequences for later brain function in the adult offspring. This idea has gained particular prominence amongst researchers interested in the etiology of neurodevelopmental disorders such as schizophrenia and autism. Approximately 10 years ago we proposed that developmental vitamin D (DVD) deficiency may explain several epidemiological features of this disease, most noticeably the winter/spring season of birth effect. In 2003 we published results from our first study indicating there were structural changes in how the brain develops in these offspring. Since then we have firmly established that DVD deficiency not only affects brain cell differentiation and gross anatomy but also produces alterations in behavior in these offspring as adults. In this chapter we describe how we came to construct the model we use today. Over the past 7 years the model has proved informative producing both structural brain changes (ventriculomegaly) and behavioral alterations (hyperlocomotion in response to NMDA antagonists) that are thought to be relevant to schizophrenia.

Systemic Epstein-Barr virus-positive (EBV+) T-cell lymphoproliferative disorder of childhood is a recently described entity. The majority of such cases have been reported from Asia, which suggests an underlying genetic predisposition. We analyzed the clinicopathologic characteristics of 5 children with EBV+ T-cell lymphoid proliferations evaluated and treated at our institute over a 2-year period. There were 3 males and 2 females of Latino ( n = 4) or Caucasian ( n = 1) heritage with a median age of 5 years (age range 2–18 years). All patients presented with EBV infection (acute, n = 4) with elevated serum EBV viral loads at the time of diagnosis and had systemic manifestations, including fever, hepatosplenomegaly, and pancytopenia. The bone marrow biopsies showed EBV+/CD8+ T-cell lymphocytosis in all patients, with variable degrees of histiocytosis, plasmacytosis, and hemophagocytosis. Interestingly, there was marked and consistent depletion of mature and precursor B cells in the marrow (

Cytogenetic abnormalities of chromosome 12p involving the TEL/ETV6 gene are observed in a variety of hematopoietic neoplasms including acute leukemias, myelodysplastic syndromes, and myeloproliferative disorders. Karyotypic aberrations, including rearrangements, deletions, and amplifications of chromosome 12p, have been documented in B-cell non-Hodgkin lymphoma; however, rearrangements targeting TEL have rarely been reported. Here we describe a diffuse large B- cell lymphoma that had a complex karyotype including t(9;12)(q22;p13), which was confirmed by fluorescence in situ hybridization to represent rearrangement of TEL. Additional cytogenetic abnormalities included t(3;14)(q27;q32) involving the variant, alternative breakpoint region of the BCL6 gene and del(6)(q13q23), resulting in the loss of 1 allele of BLIMP1. This case reiterates the importance of correlating morphologic and phenotypic findings with the results of cytogenetic analysis to avoid errors in diagnosing hematologic neoplasms and highlights the rare association of B-cell non- Hodgkin lymphoma with aberrations of TEL.

Regulation of neural proliferation is an essential component of brain formation and is driven by both intrinsic cell cycle and extrinsic growth and trophic molecules. Among the cell cycle proteins, understanding of the relative roles of the G1-phase active cyclins D2 and D1 (cD2 and cD1) has been hampered by lack of data regarding their expression patterns. In this study, cD2 immunoreactivity was examined in the neocortex, ganglionic eminences/ striatum, and hippocampal formation from embryonic day 12.5 until postnatal day 60 to more precisely characterize the expression of this protein during forebrain development. The localization of cD1 was also immunohistologically mapped for comparison. Throughout forebrain development, both overlapping and nonoverlapping protein expression of these cyclins suggests the presence of shared and unique cell cycle requirements for neurogenesis that distinguishes progenitor pools.