Modulation of dendritic spine development and plasticity by BDNF and vesicular trafficking: fundamental roles in neurodevelopmental disorders associated with mental retardation and autism

The process of axonal and dendritic development establishes the synaptic circuitry of the central nervous system (CNS) and is the result of interactions between intrinsic molecular factors and the external environment. One growth factor that has a compelling function in neuronal development is the neurotrophin brain-derived neurotrophic factor (BDNF). BDNF participates in axonal and dendritic differentiation during embryonic stages of neuronal development, as well as in the formation and maturation of dendritic spines during postnatal development. Recent studies have also implicated vesicular trafficking of BDNF via secretory vesicles, and both secretory and endosomal trafficking of vesicles containing synaptic proteins, such as neurotransmitter and neurotrophin receptors, in the regulation of axonal and dendritic differentiation, and in dendritic spine morphogenesis. Several genes that are either mutated or deregulated in neurodevelopmental disorders associated with mental retardation have now been identified, and several mouse models of these disorders have been generated and characterized. Interestingly, abnormalities in dendritic and synaptic structure are consistently observed in human neurodevelopmental disorders associated with mental retardation, and in mouse models of these disorders as well. Abnormalities in dendritic and synaptic differentiation are thought to underlie altered synaptic function and network connectivity, thus contributing to the clinical outcome. Here, we review the roles of BDNF and vesicular trafficking in axonal and dendritic differentiation in the context of dendritic and axonal morphological impairments commonly observed in neurodevelopmental disorders associated with mental retardation

Synaptic Wnt signaling—a contributor to major psychiatric disorders?

Wnt signaling is a key pathway that helps organize development of the nervous system. It influences cell proliferation, cell fate, and cell migration in the developing nervous system, as well as axon guidance, dendrite development, and synapse formation. Given this wide range of roles, dysregulation of Wnt signaling could have any number of deleterious effects on neural development and thereby contribute in many different ways to the pathogenesis of neurodevelopmental disorders. Some major psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorders, are coming to be understood as subtle dysregulations of nervous system development, particularly of synapse formation and maintenance. This review will therefore touch on the importance of Wnt signaling to neurodevelopment generally, while focusing on accumulating evidence for a synaptic role of Wnt signaling. These observations will be discussed in the context of current understanding of the neurodevelopmental bases of major psychiatric diseases, spotlighting schizophrenia, bipolar disorder, and autism spectrum disorder. In short, this review will focus on the potential role of synapse formation and maintenance in major psychiatric disorders and summarize evidence that defective Wnt signaling could contribute to their pathogenesis via effects on these late neural differentiation processes

Detectie van submicroscopische chromosomale afwijkingen door middel van array-diagnostiek

Chromosomal microarray enables identifying small genomic deletions and duplications that are not routinely seen on karyotyping. Microarray analysis therefore has emerged as a primary diagnostic tool for the evaluation of developmental delay and structural malformations in children in the Netherlands since 2008. When invasive prenatal diagnosis is indicated, because of ultrasound abnormalities and/or an increased risk for common aneuploidies (trisomy 21, 18 or 13) at first trimester screening, microarray analysis instead of conventional karyotyping will be applied when targeted molecular rapid aneuploidy detection reveals no abnormalities. Microarray analysis provides around 12-15% extra diagnosis in cases of mental retardation and/or structural abnormalities and it can provide 6% extra diagnosis in prenatal samples with a normal karyotype. Besides finding evident causative abnormalities, microarray analysis increases the detection rates of VOUS (variants of unknown significance) that, in particular during a pregnancy, induce emotional burden en counselling difficulties. Furthermore, CNVs that are pathogenic but not related with the phenotype (e.g. deletion of an oncogene) may complicate pretest and posttest counselling as well, since these findings may have health consequences for both patient and family members. Clinicians who request microarray analysis should be aware of these implications. In this paper, two prenatal and four postnatal case reports illustrate the ability to identify more clinically relevant abnormalities, but also limitations and coincidental findings in microarray analysis.</p

Influência do índice de massa corporal e da circunferência abdominal na pressão arterial sistêmica de crianças Influence of body mass index and abdominal circumference on children's systemic blood pressure

OBJETIVO: Avaliar os níveis pressóricos em crianças e relacioná-los ao índice de massa corporal e à circunferência abdominal. MÉTODOS: Por meio de estudo prospectivo e transversal, avaliaram-se 1.408 escolares com idade entre cinco anos e dez anos e 11 meses, matriculados em escolas públicas do Município de Santo André. Foram coletados: peso ao nascer; peso e estatura, expressos como escore Z do índice de massa corporal (ZIMC) e estatura para idade (ZEI). A pressão arterial (medida única) foi aferida pelo mesmo examinador. Considerou-se: desnutrição quando ZIMC<-2, obesidade ZIMC>+2, baixa estatura se ZEI<-2; circunferência abdominal aumentada (ponto de corte >P90 para sexo e idade) e pressão arterial elevada quando superior ao percentil 90 para sexo, idade e estatura. A análise estatística incluiu o teste do qui-quadrado e o cálculo da Odds Ratio, adotando-se como significante o valor de p<0,05. RESULTADOS: A mediana de idade foi de sete anos, sendo 51% do sexo feminino. Níveis elevados foram encontrados em 19 e 12% dos escolares para a pressão arterial sistólica e diastólica, respectivamente. Verificaram-se: baixa estatura, desnutrição, obesidade e aumento da circunferência abdominal em 2,6%, 3,1%, 7,3% e 13,4% da amostra, respectivamente. A presença de obesidade foi o fator mais fortemente associado ao aumento de pressão arterial sistólica (OR 2,1; IC95% 1,3-3,3; p<0,001) e diastólica (OR 2,6; IC95% 1,6-4,3; p<0,001). A circunferência abdominal também se associou com pressão arterial sistólica elevada (OR 1,6; IC95% 1,0-2,5; p=0,027). CONCLUSÕES: A pressão arterial sistêmica elevada em crianças associa-se à obesidade e ao aumento da circunferência abdominal.<br>OBJECTIVE: To evaluate blood pressure levels in children, relating them to body mass index and abdominal circumference. METHODS: This cross-sectional prospective study enrolled 1.408 school children, aged between five and ten years and 11 months, in the municipality of Santo Andre, São Paulo, Brazil. The following variables were evaluated: birth weight, weight and height, expressed as body mass index Z score (ZBMI) and height to age Z score (ZH), and waist circumference (WC). Blood pressure was measured once by the same physician. Malnutrition was considered when ZBMI <-2, obesity when ZBMI >+2, short stature when ZH <-2, increased abdominal circumference when >P90 for age and gender, and increased blood pressure when >P90 for age, gender and height. Statistical analysis included chi-square test and Odds Ratio, being significant p<0.05. RESULTS: Mean age was seven years old, and 51% were females. High systolic blood pressure levels were observed in 19% and elevated diastolic blood pressure in 12%. Short stature, malnutrition, obesity and increased abdominal circumference were diagnosed in 2.6%, 3.1%, 7.3% and 13.4%, respectively, of the studied population. The presence of obesity was strongly associated with high systolic (OR 2.1, 95%IC 1.3-3.3; p<0.001) and diastolic blood pressure (OR 2.6, 95%IC 1.6-4.3; p<0.001). Increased abdominal circumference was also an important risk factor for high systolic blood pressure (OR 1.6; 95%IC 1.0-2.5; p=0.027). CONCLUSIONS: High blood pressure in children is associated with obesity and increased abdominal circumference