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O Transtorno de Déficit de Atenção e Hiperatividade (TDAH) é um dos transtornos neuropsiquiátricos mais prevalentes da infância caracterizado pelos sintomas de desatenção, hiperatividade e impulsividade. O TDAH é uma desordem neurocomportamental heterogênea e fenotipicamente complexa e sua etiologia ainda não foi completamente esclarecida, mas sabe-se que a interação de fatores ambientais e genéticos e o acúmulo de seus efeitos possivelmente aumenta a vulnerabilidade ao transtorno. Nesse estudo, foram investigados o imunoconteúdo de proteínas sinápticas e do desenvolvimento a partir de neurônios da região do córtex pré-frontal de animais SHR, um dos modelos animais mais validados para o estudo do TDAH. Também foi realizada uma análise morfomética do padrão de desenvolvimento dessas células ao longo de diferentes dias in vitro e o papel do BDNF, fator neurotrófico crucial para a sobrevivência e maturação das sinapses, no desenvolvimento dos neurônios SHR. A análise do imunoconteúdo da SNAP-25 mostrou aumento nos níveis dessa proteína no 2º DIV e diminuição no 5º DIV nos neurônios SHR em relação ao controle WKY, sem alterações entre as cepas nos outros dias analisados. Em relação aos níveis de sinaptofisina nos neurônios SHR, foi observado aumento somente no 5º DIV. A análise do proBDNF mostrou diminuição nos neurônios SHR no 5º DIV e aumento no 8º DIV. A imunodetecção do CREB mostrou que os neurônios SHR apresentam níveis diminuídos dessa proteína somente no 1º DIV. O receptor TrkB também apresentou alterações no seu imunoconteúdo, com aumento no 2º DIV e diminuição no 5º DIV nos neurônios SHR. O imunoconteúdo do BDNF e do TrkB fosforilado não apresentaram alterações entre as linhagens nos dias analisados. Além disso, foi realizada uma análise morfométrica de diferentes parâmetros de desenvolvimento dos neurônios ao longo de diferentes dias in vitro por meio da marcação da proteína da região somatodendrítica MAP-2. Foi observada diminuição no comprimento total dos neuritos dos neurônios SHR no 5º DIV em relação aos neurônios WKY. Também foi verificado redução no número de raízes no 2º DIV e redução no número de pontos de ramificação no 5º DIV nos neurônios SHR. As alterações observadas em proteínas que são relacionadas aos processos de sinapses e de desenvolvimento neuronal podem auxiliar na compreenssão das diferenças encontradas no padrão de desenvolvimento dos neurônios SHR. Essas modificações a nível proteico podem estar alterando o crescimento e o padrão de arborização dendrítica e implicar em modificações na funcionalidade dessas células importantes para a melhor compreensão das bases neurobiológicas do TDAH. / Attention deficit hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders of childhood characterized by symptoms of inattention, hyperactivity and impulsivity. ADHD is a heterogeneous and phenotypically complex neurobehavioral disorder with unknown etiology, but the interaction between environmental and genetic factors have been described to increase the vulnerability to the disorder. In this study, we investigated the immunocontent of synaptic and development proteins of prefrontal cortex neurons from one of the most validated animal models for the study of ADHD (SHR). We also performed a morphometric analysis along development of these cells at different days in vitro and the role of a neurotrofic factor (BDNF) in neuronal outgrowth. SNAP-25 immunocontent was increased at 2 DIV and decreased at 5 DIV in SHR neurons. Synaptophysin levels show increases only at 5 DIV in SHR neurons. The levels of proBDNF were decreased at 5 DIV and increased at 8 DIV in SHR neurons. CREB immunodetection showed that SHR neurons present decreased levels only at 1 DIV. The TrkB receptor also presented changes in immunocontent, with increase at 2 DIV and decrease at 5 DIV in the SHR neurons. Morphometric analysis during neuronal development by immunostaining with MAP-2 somatodendritic protein show decrease in total length at 5 DIV in SHR neurons in relation to WKY neurons. Besides that, SHR neurons exhibit reduction in number of roots at 2 DIV and number of branch points at 5 DIV. Changes in proteins related to synaptic processes and neuronal during development can help to understand differences found in the pattern of development of the neurons SHR. These changes at protein level may be altering neuronal outgrowth and dendritic arborization and possible involve modifications in functionality of these cells important for better understanding the neurobiological bases of ADHD.

O Transtorno de Déficit de Atenção e Hiperatividade (TDAH) é um dos transtornos neuropsiquiátricos mais prevalentes da infância caracterizado pelos sintomas de desatenção, hiperatividade e impulsividade. O TDAH é uma desordem neurocomportamental heterogênea e fenotipicamente complexa e sua etiologia ainda não foi completamente esclarecida, mas sabe-se que a interação de fatores ambientais e genéticos e o acúmulo de seus efeitos possivelmente aumenta a vulnerabilidade ao transtorno. Nesse estudo, foram investigados o imunoconteúdo de proteínas sinápticas e do desenvolvimento a partir de neurônios da região do córtex pré-frontal de animais SHR, um dos modelos animais mais validados para o estudo do TDAH. Também foi realizada uma análise morfomética do padrão de desenvolvimento dessas células ao longo de diferentes dias in vitro e o papel do BDNF, fator neurotrófico crucial para a sobrevivência e maturação das sinapses, no desenvolvimento dos neurônios SHR. A análise do imunoconteúdo da SNAP-25 mostrou aumento nos níveis dessa proteína no 2º DIV e diminuição no 5º DIV nos neurônios SHR em relação ao controle WKY, sem alterações entre as cepas nos outros dias analisados. Em relação aos níveis de sinaptofisina nos neurônios SHR, foi observado aumento somente no 5º DIV. A análise do proBDNF mostrou diminuição nos neurônios SHR no 5º DIV e aumento no 8º DIV. A imunodetecção do CREB mostrou que os neurônios SHR apresentam níveis diminuídos dessa proteína somente no 1º DIV. O receptor TrkB também apresentou alterações no seu imunoconteúdo, com aumento no 2º DIV e diminuição no 5º DIV nos neurônios SHR. O imunoconteúdo do BDNF e do TrkB fosforilado não apresentaram alterações entre as linhagens nos dias analisados. Além disso, foi realizada uma análise morfométrica de diferentes parâmetros de desenvolvimento dos neurônios ao longo de diferentes dias in vitro por meio da marcação da proteína da região somatodendrítica MAP-2. Foi observada diminuição no comprimento total dos neuritos dos neurônios SHR no 5º DIV em relação aos neurônios WKY. Também foi verificado redução no número de raízes no 2º DIV e redução no número de pontos de ramificação no 5º DIV nos neurônios SHR. As alterações observadas em proteínas que são relacionadas aos processos de sinapses e de desenvolvimento neuronal podem auxiliar na compreenssão das diferenças encontradas no padrão de desenvolvimento dos neurônios SHR. Essas modificações a nível proteico podem estar alterando o crescimento e o padrão de arborização dendrítica e implicar em modificações na funcionalidade dessas células importantes para a melhor compreensão das bases neurobiológicas do TDAH. / Attention deficit hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders of childhood characterized by symptoms of inattention, hyperactivity and impulsivity. ADHD is a heterogeneous and phenotypically complex neurobehavioral disorder with unknown etiology, but the interaction between environmental and genetic factors have been described to increase the vulnerability to the disorder. In this study, we investigated the immunocontent of synaptic and development proteins of prefrontal cortex neurons from one of the most validated animal models for the study of ADHD (SHR). We also performed a morphometric analysis along development of these cells at different days in vitro and the role of a neurotrofic factor (BDNF) in neuronal outgrowth. SNAP-25 immunocontent was increased at 2 DIV and decreased at 5 DIV in SHR neurons. Synaptophysin levels show increases only at 5 DIV in SHR neurons. The levels of proBDNF were decreased at 5 DIV and increased at 8 DIV in SHR neurons. CREB immunodetection showed that SHR neurons present decreased levels only at 1 DIV. The TrkB receptor also presented changes in immunocontent, with increase at 2 DIV and decrease at 5 DIV in the SHR neurons. Morphometric analysis during neuronal development by immunostaining with MAP-2 somatodendritic protein show decrease in total length at 5 DIV in SHR neurons in relation to WKY neurons. Besides that, SHR neurons exhibit reduction in number of roots at 2 DIV and number of branch points at 5 DIV. Changes in proteins related to synaptic processes and neuronal during development can help to understand differences found in the pattern of development of the neurons SHR. These changes at protein level may be altering neuronal outgrowth and dendritic arborization and possible involve modifications in functionality of these cells important for better understanding the neurobiological bases of ADHD.

Le glufosinate d’ammonium (GLA) est un herbicide largement utilisé dans l'agriculture. Comme cela est le cas pour la plupart des pesticides, ses effets neurotoxiques et développementaux n'ont été que partiellement étudiés. L'exposition précoce des pesticides peut affaiblir la structure de base du développement du cerveau et provoquer des changements permanents conduisant un large éventail d'effets à long terme sur la santé et/ou sur le comportement. Mes travaux de thèse ont permis de montrer que l’exposition périnatale à de faibles doses de GLA induisait des perturbations de la neurogenèse et de la migration des neuroblastes au niveau de la zone sous ventriculaire vers les bulbes olfactifs. De plus l’analyse transcriptomique cérébrale montre une modification significative de l’expression de nombreux gènes responsables de la dynamique du cytosquelette impliqué dans la régulation de la migration des neuroblastes. Etant un analogue structural du glutamate, le GLA pourrait agir sur le cytosquelette via la modification de la polyglutamylation de la tubuline. Cette hypothèse expliquerait les altérations cellulaires observées. Par ailleurs, avons mis en évidence dans cette étude, des troubles du comportement des souris exposées semblables à ceux observables chez les modèles murins des « troubles du spectre autistique » (ASD-like). / Glufosinate ammonium (GLA) is one of the most widely used herbicides in agriculture. As for almost all pesticides, potential adverse effects of GLA have not been investigated in the brain developmental neurotoxicity perspective. Indeed, early pesticides exposure may weaken the developing brain and cause permanent brain alteration which could lead to a wide range of the lifelong effects on health and/or behavior. As an illustration, we showed that perinatal exposure to low doses of GLA induced behavioral defects in mice adulthood, characterized by many similarities with Autism Spectrum Disorders phenotype. My thesis deals with the molecular aspect of this perinatal GLA exposure. I demonstrated that GLA induced disturbances of proliferation and neuroblast migration from the subventricular zone to the olfactory bulbs. These defects were associated with significant change in the expression of many genes involved in neuroblast migration and cytoskeleton regulation as observed by brain transcriptome analysis. I showed that GLA act on the cytoskeleton through modification of polyglutamylation of tubulin which lead to cell division/migration disturbances and cell differentiation defect. My work thus provides a new molecular link between pre- and post-natal exposure to the herbicide GLA and the onset of ASD like phenotype later in life. It also raises the fundamental concerns about the ability of current safety testing to assess risks of pesticide exposure during critical developmental periods.

Several studies show that physical activity has positive effects for children with autism. Therefore, I chose to investigate the form of adaptions student in autism spectrum in the subject of sports and health and what conditions the physical education teachers have to create a favorable environment for student with autism. Through a qualitative research method with teachers in physical education and health, the material has been collected with semi structured interviews. The results show how teachers adapt teaching to student with autism spectrumdisorders. Physical education and health teachers work in different ways. The adaption can consist of preparation, the student’s special interests, structure, participation/involvement, andclarity in the teaching. Based on the discussion, all students are different and the teachers need to adapt the student’s needs. / Flertal studier visar att fysisk aktivitet har positiva effekter för barn med autism. Därför valde jag att undersöka vilken form av anpassningar elever inom autismspektrumet i ämnet idrott och hälsa och vilka förutsättningar idrottslärarna har för att skapa en gynnsam miljö för elever med autism. Genom en kvalitativ forskningsmetod med lärare inom idrott och hälsa har materialet samlats in via semistrukturerade intervjuer. I resultatet framkommer det hur lärarna anpassar undervisningen till elever med autismspektra. Idrott och hälsa lärarna arbetar på olika sätt för att anpassa undervisningen. Anpassningen kan bestå av förberedelser, elevensspecialintressen, struktur, delaktighet/involvering samt tydlighet i undervisningen. Utifrån diskussionen är alla elever olika och lärarna behöver anpassa elevens behov.

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La schizophrénie précoce (SP), trouble rare (~0,01%) du neurodéveloppement est décrite sous deux formes : la schizophrénie très précoce, avant 13 ans et celle de l’adolescence entre 13 et 18 ans. Le diagnostic complexe à poser et les méconnaissances de la SP font supposer qu’elle est sous diagnostiquée et que les propositions thérapeutiques et de prise en charge sont encore peu spécifiques. Nous avons mené une première étude épidémiologique de prévalence pour : (1) évaluer le taux de sujets répondant au diagnostic de SP dans un échantillon de 302 enfants issus des structures médico-sociales et sanitaires en région PACA ; (2) caractériser sur le plan clinique et neurocognitif les enfants avec SP ; (3) évaluer le taux d’enfants répondant à la fois aux diagnostics de SP et de Troubles du Spectre Autistique (TSA). Puis, une deuxième étude, du sous-groupe d’enfants ayant une comorbidité SP et TSA, a exploré la psychopathologie, la personnalité et les capacités cognitives des membres du 1er degré des familles de ces enfants. Les résultats sont : un taux de 8,9% de patients avec SP, dont 59,3% de garçons âgés de 12,4 ans en moyenne (ET=3,2), avec un Quotient Intellectuel moyen de 72,5 (ET=21,4), des hallucinations (82,8%), des symptômes négatifs (70%), une comorbidité avec un TSA (41.2%) et des traitements neuroleptiques (51,5%). L’étude des familles a montré que les mères ont plus de troubles de la personnalité, de traits autistiques, de pathologies psychiatriques et un QI moyen plus faible. La constitution et le phénotypage de cette cohorte a permis dans les suites de ce travail, de lancer une étude génétique familiale avec séquençage d’exome des parents et des enfants avec SP. / Early Onset Schizophrenia (EOS), a rare neurodevelopmental disorder (≈0.01%) is categorized into two types: Very Early Onset Schizophrenia, before age 13 and Adolescent Schizophrenia between ages 13 and 18. This diagnosis is a difficult one to make and considering the lack of knowledge on EOS, we can presume that it is in fact under-diagnosed and that our treatment and management options are still not very specific. We conducted a first epidemiological prevalence study consisted in evaluating: (1) the rate of subjects with EOS diagnostic criteria among 302 children who receive care in psychosocial and sanitary care facilities in the PACA region; (2) the clinical and neurocognitive characteristics of those children with EOS; (3) the rate of children with both EOS and ASD criteria within the same sample. In a second study, focusing on a subgroup of children with comorbid EOS and ASD, we analyzed first-degree relatives from a psychopathological, personality and cognitive viewpoint. The results are: a high rate of patients (8.9%) with an EOS diagnosis, a male gender majority (59.3%), an average age of 12.4 (SD=3.2), an average intelligence quotient of 72.5 (SD=21.4), a rate of 82.8% of subjects with hallucinations, 70% with EOS negative symptoms, 41.2% with comorbid autism, and 51.5% with antipsychotic medications. The study of family members shows that mothers have a higher rate of personality disorders, autistic traits and psychiatric disorders, as well as a lower average IQ. The creation and the characterization of a phenotype of this cohort have led to a family-genetic analysis based on exome sequencing in the parents and children with EOS following this study.

La mémoire autobiographique est vue comme un ensemble d'informations et de souvenirs personnels permettant de construire un sentiment d'identité. Elle se développe progressivement et apparaît très sensible aux pathologies neurodéveloppementales. La mémoire autobiographique est intimement liée au Soi lui permettant d'encoder et de récupérer toutes ses représentations et expériences. Ainsi, le Soi se constitue d'aspects explicites comprenant la mémoire autobiographique mais également d'aspects plus implicites relatifs aux expériences corporelles du sujet. L'atteinte des aspects implicites et explicites du Soi pourrait rendre compte de certains symptômes psychotiques et des difficultés d'adaptation des patients atteints de schizophrénie. La schizophrénie est une pathologie neurodéveloppementale qui débute à la fin de l'adolescence mais qui pourrait puiser son émergence dans des stades bien plus précoces. Le premier épisode psychotique qui signe l'entrée dans la phase active de la maladie est généralement précédé par une phase « prodromique » où des symptômes cliniques sont présents à un niveau infraliminaire du seuil de psychose. Ces sujets sont qualifiés de sujets à ultra haut risque de psychose (UHR). Les troubles du Soi sont bien documentés dans la schizophrénie, néanmoins très peu de données sont disponibles concernant les sujets UHR. Le but de cette thèse est multiple : (i) mesurer l'impact des anomalies neurodéveloppementales sur la mémoire autobiographique, (ii) objectiver des déficits de la mémoire autobiographique dès la phase prodromique, (iii) évaluer l'ensemble des composantes du Soi afin d'investiguer leurs interactions et l'impact des anomalies développementales sur celles-ci. Nous avons ainsi effectué trois études. Notre première étude a investigué le lien entre le poids des anomalies neurodéveloppementales et la mémoire autobiographique en comparant deux pathologies neurodéveloppementales, une à début tardif : la schizophrénie, et l'autre à début précoce : les troubles du spectre autistique. Nous avons pu mettre en évidence un pattern de performances similaires entre les deux populations bien que les mécanismes responsables des troubles en mémoire autobiographique apparaissent distincts. Dans notre deuxième étude, nous avons comparé les performances autobiographiques de patients atteints de schizophrénie par rapport à celles de sujets UHR. Nos résultats révèlent un déficit de la mémoire autobiographique aussi sévère chez les sujets UHR que chez les patients atteints de schizophrénie mettant ainsi en évidence une atteinte de cette fonction en amont du premier épisode psychotique. Dans la lignée de ces résultats, nous avons conduit une troisième étude. Le but étant de situer la mémoire autobiographique dans un contexte plus large, celui du Soi, tout en intégrant une composante développementale. Nous avons élaboré et proposé une batterie d'investigation examinant différents aspects du Soi implicites et explicites, combiné à l'évaluation d'anomalies du neurodéveloppement. Celle-ci a été administrée chez des sujets UHR en comparaison à des patients atteints de schizophrénie. Au final, nos résultats révèlent un impact de la charge neurodéveloppementale sur les différents aspects du Soi, la pertinence d'investiguer au sein d'un même protocole ces différents aspects et la présence d'anomalies du Soi déjà présents chez les sujets UHR, constituant potentiellement des marqueurs prédicteurs de transition psychotique et permettant d'améliorer la détection précoce de ces sujets et leur prise en charge. / Autobiographical memory is delineated as a set of personal information and experiences to build a sense of identity. It develops gradually and appears very sensitive to neurodevelopmental disorders. Autobiographical memory is intimately linked to the self, enabling it to encode and retrieve all its representations and experiences. Thus, the self is constituted of explicit aspects including autobiographical memory but also by more implicit aspects relating to the subject's body. Implicit and explicit self-aspects alterations may account for certain psychotic symptoms and adaptation difficulties in patients with schizophrenia. Schizophrenia is a neurodevelopmental disorder that begins at the end of adolescence but which could emerge in much earlier stages. The first psychotic episode that signs the beginning of the active phase of schizophrenia is usually preceded by a "prodromal phase" during which clinical signs are present at a sub-threshold level. Individuals experiencing these signs are considering as Ultra High Risk of psychosis (UHR). Self-disorders are well documented in schizophrenia, however very little is known regarding UHR subjects. The aim of this thesis is multiple: (i) to measure the impact of neurodevelopmental anomalies on autobiographical memory, (ii) to objectify autobiographical memory deficits in the prodromal phase, (iii) to evaluate all the self-components in order to investigate their interactions and the impact of developmental anomalies. We have conducted three studies. Our first study investigated the relationship between neurodevelopmental anomalies and autobiographical memory by comparing two neurodevelopmental disorders, one with late onset: schizophrenia and the other with early onset: autism spectrum disorders. Results revealed a pattern of similar performances between the two populations although the mechanisms responsible for autobiographical memory impairment do not appear the same. In our second study, we compared the autobiographical performances of patients with schizophrenia compared to those of UHR subjects. Our results highlighted a deficit of autobiographical memory as severe in UHR subjects as in patients with schizophrenia, thus revealing an impairment of this function upstream of the first psychotic episode. In line with these results, we conducted a third study. The aim was to situate the autobiographical memory in a wider context, the multi-componential Self, while integrating a developmental component. We developed and proposed a battery investigating different self-components, combined with the assessment of neurodevelopmental anomalies. This battery was administered in UHR subjects compared to patients with schizophrenia. Finally, our results reveal an impact of neurodevelopmental abnormalities on the different self-aspects, the relevance of investigating these different self-aspects within the same protocol and the presence of self-abnormalities already present in the UHR subjects, constituting potentially predictive marker of psychotic transition and improving the early detection of these subjects and the development of healthcare and reinsertion programs.

Contexte théorique : L’encéphalopathie hypoxique ischémique (EHI) est une condition du nouveau-né dans laquelle les mécanismes des variables métaboliques ne sont pas totalement compris. Cette population est particulièrement à risque d’hypo- ou d’hyperglycémie néonatales (HHN). Devant le manque de données sur le fonctionnement métabolique à la suite d’une EHI, cette étude vise à déterminer l’association entre une HHN et l’activité cérébrale mesurée par électroencéphalographie (EEG). Méthodologie : 49 participants avec EHI ont été recrutés au CHU Sainte-Justine peu après leur naissance. Ils ont été monitorés en continu à l’aide de l’EEG et des segments d’intérêt se retrouvant dans les 48 premières heures de vie ont été analysés. L’anormalité de l’activité cérébrale est déterminée selon une analyse quantitative du niveau de discontinuité caractérisée par une proportion de faibles amplitudes (seuils de 25, 15, 12,5, 10 et 7,5 uV) dans le tracé EEG. Les données de glycémie ont été recueillies de façon intermittente par le biais de prises de sang et de glucomètres de chevet. Les participants ont été répartis en 4 groupes : normoglycémie, hyperglycémie, hypoglycémie et glycémie variable (hypo- et hyper-). Résultats : L’analyse de covariation non -paramétrique a relevé une différence significative entre les ratios de discontinuité pour le seuil de 15 uV (F = 3,070 p = 0,037). Les analyses de comparaisons appariées ont montré une différence positive entre le groupe VARIABLE et le groupe contrôle (NORMO-) pour tous les seuils ainsi qu’une différence positive entre le groupe HYPER- et le groupe contrôle pour 4 des 5 seuils (25, 15, 12,5 et 7,5 uV). Aucune différence n’a été relevé entre le groupe HYPO- et le groupe contrôle pour tous les seuils. Conclusions : La variabilité glycémique et l’hyperglycémie seule ont été montrées comme étant associées à une activité cérébrale altérée caractérisée par un tracé de plus faible amplitude mesurée avec l’EEG. / Background: Hypoxic ischemic encephalopathy (HIE) is a newborn condition in which the underlying mechanisms still require further understanding. This clinical population is particularly prone to neonatal hypo- and hyperglycemia (NHH). Given the need to improve our understanding of metabolic functioning following HIE, this study aims to determine the association of NHH on the brain’s background electrophysiological activity measured by electroencephalography (EEG). Methodology: Forty-nine newborns with HIE were recruited at Sainte-Justine University Hospital Center. Continuous EEG monitoring was started as soon as possible and segments of interest in the first 48h of life were analyzed. Brain activity was quantitatively assessed according to an index of discontinuity characterized by the proportion of low EEG amplitudes per segment (< 25, 15, 12.5, 10 and 7.5 uV cutoffs). Glucose measurements were intermittently collected using blood samples and bedside glucometers and were retrospectively retrieved from medical charts. Participants were separated in 4 groups : normoglycemia, hyperglycemia, hypoglycemia and both (hyper- and hypo-). Results: The non-parametric covariance analyses revealed a significant difference between the discontinuity index for the 15 uV threshold (F = 3.070 p = 0.037). The pairwise comparisons showed a positive difference between the group BOTH and the control group (NORMO-) for every thresholds, the labile glucose group having a higher discontinuity index. A similar difference was found between the HYPERGLYCEMIA group and the control group for 4 out 5 thresholds (25, 15, 12.5 and 7.5 uV). No difference was found between the HYPOGLYCEMIA group and the control group. Conclusion: An abnormal glycemic profile, particularly glucose lability and hyperglycemia alone, were shown to be associated with abnormal brain activity characterized by a higher discontinuity index on the EEG.