Williams Beuren syndrome Syndrome (WBS) and 7q11.23 Duplication Syndrome (Dup7) are rare neurodevelopmental disorders associated with a range of cognitive and behavioural symptoms, caused by the deletion and duplication, respectively, of 26 genes on human chromosome 7q11.23. I have studied the effects of deletion or duplication of two candidate genes, GTF2I and GTF2IRD1, on neural stem cell growth and neurogenesis using cultured primary neuronal precursors from mouse models with gene copy number changes. I found that the number of neuronal precursors and committed neurons was directly related to the copy number of these genes in the mid-gestation embryonic cortex. I further found that in late-gestation embryos, cortical thickness was altered in a similar gene dose-dependent manner, in combination with layer-specific changes in neuronal density. I hypothesize that some of the neurological features of WS and Dup7 stem from these impairments in early cortical development.

Williams Beuren syndrome Syndrome (WBS) and 7q11.23 Duplication Syndrome (Dup7) are rare neurodevelopmental disorders associated with a range of cognitive and behavioural symptoms, caused by the deletion and duplication, respectively, of 26 genes on human chromosome 7q11.23. I have studied the effects of deletion or duplication of two candidate genes, GTF2I and GTF2IRD1, on neural stem cell growth and neurogenesis using cultured primary neuronal precursors from mouse models with gene copy number changes. I found that the number of neuronal precursors and committed neurons was directly related to the copy number of these genes in the mid-gestation embryonic cortex. I further found that in late-gestation embryos, cortical thickness was altered in a similar gene dose-dependent manner, in combination with layer-specific changes in neuronal density. I hypothesize that some of the neurological features of WS and Dup7 stem from these impairments in early cortical development.

Assessment of executive functioning in neurodevelopmental disorders (e.g., autism) is a crucial aspect of neuropsychological evaluations. The executive functions are accomplished by the supervisory attentional system (SAS) and include such processes as inhibition, switching, and planning. Autism spectrum disorder (ASD) tends to present similarly to other neurodevelopmental disorders (e.g., ADHD). For example, ASD and ADHD may share similar etiological underpinnings in the frontostriatal system of the frontal lobe. Research on executive functioning in ASD has been mixed, thus the precise nature of executive functioning deficits in ASD remains equivocal. In recent years, simulation technologies have emerged as an avenue to assess neurocognitive functioning in individuals with neurodevelopmental disorders impacting frontostriatal function. Simulation technology enables neuropsychologists to assess neurocognitive functioning within a testing environment that replicates environments in which the subject is likely to be in everyday life, as well as present controlled, real-world distractions, which may be better able to tap “hot” executive functions. A Virtual Classroom Continuous Performance Test (CPT) has been used successfully to assess attention in individuals with neurodevelopmental disorders impacting frontostriatal function. The current study aimed to investigate executive functioning in individuals with high functioning ASD using a new construct driven Stroop assessment embedded into the Virtual Classroom. Group differences were found in the Virtual Classroom with distractions condition, indicating individuals with ASD may be more vulnerable to external interference control than neurotypical individuals.

Compreender as bases do comportamento social e do desenvolvimento socioafetivo humano é essencial tanto para indivíduos com desenvolvimento típico (DT) quanto com transtornos neuropsiquiátricos. A Síndrome de Williams (SW) é uma condição neurogenética rara ocasionada pela deleção de aproximadamente 28 genes no cromossomo 7q11.23. A sintomatologia inclui desde dismorfismos faciais a alterações do funcionamento cognitivo e socioafetivo, com a presença de deficiência intelectual de grau leve a moderado. O processamento de estímulos afetivos tem sido foco de grande interesse em indivíduos com SW. Apesar de parte das pesquisas apontarem que esta população tem habilidade preservada de reconhecimento de expressões facias de emoções positivas e prejuízos no reconhecimento de emoções negativas, este ainda não é um campo consensual. Ao mesmo tempo, estudos indicam maior interesse desta população em relação a música e diferenças no neuroprocessamento de trechos musicais com valência afetiva. O presente trabalho teve por objetivo caracterizar o processamento de estímulos afetivos musicais e visuais em crianças e adolescentes com Síndrome de Williams. O Estudo I buscou validar trechos musicais com valência afetiva em cultura brasileira e analisar o efeito do treino musical na compreensão de emoções em música. Músicas com valência afetiva foram avaliadas pelos participantes de maneira correspondente à emoção pretendida pelo compositor e de forma similar entre as populações brasileiras e canadenses. O efeito do treino musical sobre a habilidade de reconhecer as emoções em música tiveram maior impacto em emoções com maior grau de dificuldade para os participantes como todo. O Estudo II visou caracterizar o perfil musical de crianças e adolescentes com SW e diferenciar o processamento de estímulos afetivos musicais em crianças e adolescentes com SW com as de DT. Pessoas com SW foram avaliadas com maior habilidade musical global. Não foram encontradas diferenças no que diz respeito ao interesse por atividades musicais. O Estudo III teve como objetivos diferenciar habilidade de reconhecimento de emoções o padrão de rastreamento do olhar frente a estímulos afetivos visuais em crianças e adolescentes com SW e SW com sintomas de TEA (SW/TEA). Pessoas com SW desprenderam maior tempo de fixação nos olhos e em faces alegres quando comparadas a faces tristes. Resultados indicam diferença no reconhecimento de emoções e rastreamento de olhar em indivíduos com SW/TEA. Padrão de reconhecimento em estímulos musicais e visuais foi semelhante na população SW, com acentuado prejuízo no reconhecimento de emoções negativas e preservação do reconhecimento de emoções positivas. Este achado reforça a modularidade do processamento neurológico das emoções básicas. Crianças com SW reconheceram mais facilmente estímulos musicais de valência positiva em comparação aos visuais sugerindo que o domínio da música seja um ponto de força desta população / Understand the foundation of social behavior and human social and affective development is essential for both individuals with typical developmental (TD) and neuropsychiatric disorders. Williams Syndrome (WS) is a rare neurogenetic condition caused by the deletion of approximately 28 genes on chromosome 7q11.23. The symptomatology includes from facial dysmorphisms to changes in cognitive and social and affective functioning, with the presence of mild to moderate intellectual deficiency. The processing of affective stimuli has been a focus of great interest in individuals with WS. Although part of the research indicates that this population has preserved ability to recognize face expressions of positive emotions and impairment in the recognition of negative emotions, this is not yet a consensual field. At the same time, studies indicate greater interest of this population in relation to music and differences in the neuroprocessing of musical excerpts with affective valence. The present work aimed to characterize the processing of musical and visual affective stimuli in children and adolescents with Williams Syndrome. Study I sought to validate musical excerpts with affective valence in Brazilian culture and to analyze the effect of musical training on the understanding of emotions in music. Songs with affective valence were evaluated by the participants corresponding to the emotion pretended by the composer and similarly between the Brazilian and Canadian populations. The effect of musical training on the ability to recognize emotions in music has had a greater impact on emotions with a greater degree of difficulty for participants as a whole. Study II aimed to characterize the musical profile of children and adolescents with WS and to differentiate the processing of musical affective stimuli in children and adolescents with WS compered to TD. People with WS were assessed with greater overall musical ability. No differences were found regarding the interest in musical activities. The aim of Study III was to differentiate between the ability to recognize emotions and the pattern of eye tracking in relation to visual affective stimuli in children and adolescents with SW and WS with ASD symptoms. People with SW gave more fixation time to the eyes and happy faces when compared to sad faces. Results indicate difference in the recognition of emotions and eye tracking in individuals with SW / ASD. Recognition pattern in musical and visual stimuli was similar in the WS population, with marked impairment in the recognition of negative emotions and preservation of the recognition of positive emotions. This finding reinforces the modularity of neurological processing of basic emotions. Children with WS recognized easily positive musical stimuli compared to visual ones suggesting that the domain of music is the strength of this population

The development of the central nervous system is dysregulated in neurodevelopmental disorders such as intellectual disability, autism spectrum disorder, and epilepsy. These three disorders have different clinical features, yet there is high comorbidity between them. They can be difficult to study due to their highly complex aetiologies, however there are various monogenic diseases that can cause all of them, including SYNGAP1 haploinsufficiency where the synaptic guanosine triphosphatase (GTPase)-activating protein (SYNGAP) protein levels are highly reduced; Fragile X syndrome where the fragile X mental retardation protein (FMRP) is no longer translated; and DNM1 epileptic encephalopathy where mutations in the Dynamin1 gene alter the protein function. These monogenic conditions are synaptopathies as the proteins affected play important roles in synapse stability and neurotransmission. Because of the high comorbidity between these disorders, it is hypothesised that there may be a common mechanism underlying them. We hypothesise that a deficit in presynaptic vesicle recycling may be part of a common mechanism underlying intellectual disability, autism spectrum disorder, and epilepsy especially in SYNGAP1 haploinsufficiency, Fragile X syndrome, and DNM1 epileptic encephalopathy. Using various fluorescent presynaptic activity reporters including synaptic pHluorins, tetramethylrhodamine dextran and calcium dyes to compare presynaptic activity in in vitro models of these monogenic conditions, we found differences in synaptic vesicle (SV) endocytosis in the genetically altered conditions compared to wildtype controls. We observed various SV endocytosis defects in clathrin-mediated endocytosis (CME) or activity-dependent bulk endocytosis (ADBE) in our models. We observed enhanced CME in SynGAP1 KO mouse hippocampal neurons. This enhanced SV endocytosis was accompanied by decreased SV cargo on the plasma membrane. Rat SynGAP1 KO hippocampal neurons did not display enhanced SV endocytosis, nor did neurons with the GTPase-activating (GAP) domain of SynGAP deleted. This was perhaps due to the altered time course of development between these rodent species. In mouse and rat models of Fragile X syndrome, CME was not altered compared to wildtype controls. However, in a rat model, we observed fewer nerve terminals undergoing ADBE which is the dominant SV endocytosis mode during elevated neuronal activity. De novo epileptic encephalopathy-associated mutations in DNM1 had differential effects on SV recycling through both CME and ADBE. Mouse hippocampal neurons overexpressing Dyn1R237W, Dyn1I289F and Dyn1H396D all showed less CME compared to overexpression of Dyn1WT. Moreover, fewer nerve terminals overexpressing Dyn1H396D were found to undergo ADBE. We also found that a large-conductance potassium (BK) channel opener can accelerate clathrin-mediated endocytosis and thus may be able to rescue the impaired SV endocytosis caused by these mutants. Although there is not yet a common underlying pathway at the presynaptic level between these conditions, SV recycling dysfunction is present across all of these models. Furthermore, we propose an axis of pathophysiology model where optimal SV endocytosis is required for optimised neural performance. We propose that either decreased or increased SV endocytosis can lead to the synaptic dysfunction observed in these models.

Submitted by Suzana Dias (suzana.dias@famerp.br) on 2018-11-06T15:03:20Z No. of bitstreams: 1 MariaFernandaLopesFerreira_dissert.pdf: 1193846 bytes, checksum: 166134b8cb10ff377557a520ecc3c877 (MD5) / Made available in DSpace on 2018-11-06T15:03:20Z (GMT). No. of bitstreams: 1 MariaFernandaLopesFerreira_dissert.pdf: 1193846 bytes, checksum: 166134b8cb10ff377557a520ecc3c877 (MD5) Previous issue date: 2018-05-16 / Studies have shown a high prevalence of mental disorders in child and adolescent population in Brazil, and in the world. Investigations on pre-school children behavior in the state of São Paulo, Brazil, have identified a 12.5 % prevalence of children with behavioral problems. Objective: to evaluate the behavioral development of pre-school children in a swimming program. Method: convenience sample longitudinal study, through quantitative-qualitative analysis, performed at a swimming school in the city of São José do Rio Preto. One parent or responsible for the participants has answered to CBCL / 1 1/2 and 5-year questionnaire, before and after the swimming program, classifying the children as having "clinical" or "non-clinical" problems. A p < 0. 05 significance has been used for data analysis. Results: comparing results before and after the program, children have shown a significant improvement in 6 syndromes out of the 15 assessed by CBCL. A little significant improvement has been observed in the kids’ general behavior, and, considering gender, girls have presented a slightly more important improvement than boys. Conclusion: after the proposed swimming program, the descriptive analysis has shown significant improvement in the children’s behavior compared to the statistical analysis. / Estudos constatam a alta prevalência de transtornos mentais na população infanto-juvenil no Brasil e no mundo. Investigações sobre o comportamento de crianças em idade escolar, no interior do estado de São Paulo, Brasil, identificaram uma prevalência de 12,5% de crianças com problemas de comportamento. Objetivo: avaliar o desenvolvimento comportamental de crianças pré-escolares em um programa de natação. Método: estudo longitudinal, com amostra de conveniência de 45 participantes, com analise quanti-qualitativa, realizado em uma escola de natação, na cidade de São José do Rio Preto. Os responsáveis pelos participantes responderam ao questionário Child Behavior Check List CBCL / 1 12⁄ e 5 anos, antes e depois do programa de natação, classificando-os como portadores de problemas “clínicos” e “não clínicos”, e para análise de dados adotou-se nível de significância p<0,05. Resultados: os resultados comparados pré e pós o programa mostraram uma melhora significativa em 6 síndromes das 15 comtempladas pela CBCL. Descobriu-se pouca melhora significativa no comportamento das crianças em geral e, observando por gênero, as meninas obtiveram uma melhora mais significativa em comparação com os meninos. Conclusão: houve melhora no comportamento das crianças após o programa de natação proposto, observando-se melhora considerável, na análise descritiva, em comparação com a análise estatística.

The 16p11.2 copy-number variant (CNV) represents a well-characterized, high-risk factor for autism spectrum disorder that additionally predisposes deletion carriers (16pdel) to increased head circumference, known as macrocephaly. The 16p11.2 CNV consists of 29 known genes, many of which are associated with neurobiological processes relevant for macrocephaly such as cell proliferation and apoptosis, differentiation and cell growth. Our lab’s previous work has demonstrated that induced pluripotent stem cell (iPSC)-derived neurons from 16pdel carriers show altered cellular morphology related to growth, which include increased soma size, total dendritic length and dendritic complexity. However, specific CNV genes responsible for these phenotypes have not been established. Here, we investigate the relationship between three 16p11.2 genes and the observed cellular phenotypes. We differentiated neurons from control iPSC-derived neural progenitor cells (NPCs) and used short hairpin RNA (shRNA) to reduce the expression of these CNV genes: KCTD13, MAPK3 and C16ORF53. We then assessed neuronal morphology by evaluating soma size, total dendritic length and dendritic complexity. We demonstrate that knocking down KCTD13 and C16ORF53 increases soma size and total dendrite length, respectively, similar to that observed in 16pdel iPSC-derived neurons. For this reason, we speculate that these genes may have a role in cell growth and might underlie macrocephaly. Thus, our study investigates genes in the 16p11.2 CNV that contribute to neuronal morphology, which may have a role in influencing brain size.

Individuals exposed to alcohol in utero have reduced cortical grey matter volumes. However, the underlying determinants of these reductions have not been investigated exclusively in alcohol-related neurodevelopmental disorder (ARND). Using magnetic resonance imaging scans from 121 participants (57 ARND and 64 controls) aged 8 to 16 years, cortical morphology was analyzed. Results revealed the ARND group had reduced cortical grey matter volumes, but did not differ from controls in cortical thickness. Rather, the cortical abnormalities reflected reductions in global surface area, local surface area reductions in the right occipital-temporal area and right superior temporal gyrus, as well as reduced gyrification. A significant interaction between sex and group was observed, with females showing greater reductions than males in cortical volume and surface area. Results suggest that ARND is characterized by global reductions in cortical surface area and gyrification and females are more vulnerable than males to the teratogenic effects of alcohol.

Individuals exposed to alcohol in utero have reduced cortical grey matter volumes. However, the underlying determinants of these reductions have not been investigated exclusively in alcohol-related neurodevelopmental disorder (ARND). Using magnetic resonance imaging scans from 121 participants (57 ARND and 64 controls) aged 8 to 16 years, cortical morphology was analyzed. Results revealed the ARND group had reduced cortical grey matter volumes, but did not differ from controls in cortical thickness. Rather, the cortical abnormalities reflected reductions in global surface area, local surface area reductions in the right occipital-temporal area and right superior temporal gyrus, as well as reduced gyrification. A significant interaction between sex and group was observed, with females showing greater reductions than males in cortical volume and surface area. Results suggest that ARND is characterized by global reductions in cortical surface area and gyrification and females are more vulnerable than males to the teratogenic effects of alcohol.

Recently, it has been suggested that neurodevelopmental abnormalities underlie schizophrenia. However, it has also been suggested that schizophrenia is a neurodegenerative disease as evidenced by a progressive worsening of symptoms over time. Neurodevelopmental abnormalities may, therefore, create a functionally compromised system that is more susceptible to neuronal atrophy and/or death caused by environmental factors such as stress (a known precipitant of acute psychotic episodes and exacerbant of schizophrenia). This hypothesis was tested using the putative neurodevelopmental model of schizophrenia described by Lipska 'et al'. (1993). The effects of neonatal hippocampal lesions on BDNF mRNA and NMDAR1 mRNA, factors involved in development, cell survival and cell communication, were investigated in adult rats following exposure to a physiological stressor. Apoptosis levels were also investigated in these rats to determine if neurodegeneration was present. Results demonstrate that BDNF mRNA was reduced in the prefrontal cortex and hippocampus of lesioned as compared to sham rats. Increased BNDF mRNA resulted from swim stress in both groups, but the increase in lesioned animals was more pronounced than controls. NMDAR1 mRNA was also reduced in the prefrontal cortex and CA3 and CA1 regions of the hippocampus in lesioned versus sham rats. There was an increase, however, in the dentate gyrus of lesioned versus sham rats. Swim stress increased NMDAR1 mRNA in the prefrontal cortex and decreased it in the hippocampus. There was also an increase in apoptosis in lesioned versus sham rats, with no significant increase in response to stress. Reductions in BDNF mRNA in lesioned versus control animals support the hypothesis that neurodevelopmental lesions may result in a system more susceptible to stressors. Reductions in NMDAR1 mRNA are in accordance with the NMDA glutamate receptor hypofunction theory of schizophrenia. It is possible that reductions in glutamate function can remove the inhibitory effect of GABA, thereby resulting in overexcitation of the system and a potential for neurodegeneration. Increased apoptosis supports the presence of neurodegeneration as an ongoing phenomenon. Even though the effect of acute stress on apoptosis was not significant, the very small increases demonstrated can have significant functional consequences over extended periods of time.