Engrailed (En) est un facteur de transcription important pour la mise en place de la segmentation de l’embryon et du plan d’organisation antéro-postérieur. Comme d’autres membres de la famille des homéoprotéines, Engrailed peut aussi agir comme une molécule de signalisation extracellulaire, internalisable grâce à son domaine « pénétratine » et stimulant dans la cellule cible la transcription ou la traduction des ARNm. De cette façon, Engrailed guide les axones en modifiant la traduction dans le cône de croissance axonal et l’infusion cérébrale d’Engrailed protège les neurones dopaminergiques dans un modèle de la maladie de Parkinson en augmentant la traduction de protéines mitochondriales. Des troubles cognitifs et un déficit des interactions sociales ont été observés chez les souris En1+/- et les souris En2-/-. Une augmentation de l’expression d’En2 a aussi été observée chez des patients atteints de troubles du spectre autistique. Néanmoins, le lien entre les modifications de l’expression d’Engrailed et l’autisme ne sont pas compris. L’objectif de cette thèse a été d’étendre notre connaissance des fonctions d’Engrailed dans une région télencéphalique où elle est a priori peu exprimée (l’hippocampe). Nos résultats confirment l’expression d’En1 et En2 dans l’hippocampe mature et décrivent les variations de l’expression de ces gènes au cours du développement de cette structure. En1 et En2 présentent des patrons d’expression différents pendant la première semaine postnatale et chez l’adulte suggérant que des variations du dosage génique d’Engrailed sont liées à certaines phases du développement, en particulier au début de la synaptogenèse. Nous avons également découvert que dans les cultures de cellules d’hippocampe Engrailed est exprimé dans les neurones et que son expression est plus forte dans les neurones GABA-ergiques, notamment dans leurs prolongements dendritiques et axonaux. Nous avons constaté qu’un excès d’Engrailed (décrit dans certains cas de TSA) augmente la complexité dendritique ainsi que la densité des épines dendritiques plastiques mais sans augmenter parallèlement la formation de synapses matures excitatrices. Nous avons observé des variations de densité des épines dendritiques chez les souris En2-/- et les souris En1+/-, ce qui confirme l’implication d’Engrailed dans leur formation ou leur stabilisation. Si dans nos conditions expérimentales l’excès d’Engrailed ne modifie pas la densité des synapses, un mutant d’Engrailed qui présente une interaction réduite avec eIF4E est moins efficace qu’Engrailed pour augmenter la densité des épines et diminue la densité des boutons présynaptiques et le synaptic matching. Ces résultats indiquent que l’interaction avec eIF4E régule au moins en partie les effets d’Engrailed sur la spinogenèse et suggèrent également une implication d’Engrailed dans la formation ou la stabilisation des boutons présynaptiques. Le rôle clef d’eIF4E dans la traduction permet de postuler que certains effets d’Engrailed observés dans notre étude pourraient dépendre de la synthèse protéique. Nos résultats montrent à cet égard qu’Engrailed augmente la synthèse protéique dans les neurones d’hippocampe. Cette traduction est différente de celle induite par la LTP chimique (LTPc) car insensible à l’action des oligomères synthétiques d’AβO, responsables sous leur forme naturelle de synaptopathies dans le contexte de la maladie d’Alzheimer. Engrailed permet également de restaurer la traduction défaillante de neurones issus de souris TG2576, modèles de la maladie d’Alzheimer. Dans leur ensemble, nos résultats identifient Engrailed comme un nouvel acteur de la plasticité dendritique. Ils révèlent qu’un excès d’Engrailed au cours de la synaptogenèse modifie les caractéristiques des dendrites, une situation susceptible d’altérer les caractéristiques fonctionnelles du réseau dendritique dans une situation de surexpression pathologique de la protéine. (...) / Engrailed (En) is an important transcription factor in embryo’s segmentation and anterior-posterior axis establishment during early embryogenesis. As several homeoproteins, Engrailed can act as an extracellular signalling molecule which can be internalized by target cells thanks to its penetratin domain and act through transcriptional and/or translation dependent mechanisms. Engrailed has for instance, translation-dependent effects on axonal guidance and cerebral infusion of Engrailed protects dopaminergic neurons in a Parkinson disease model by increasing mitochondrial protein translation. Also, cognitive defects were observed in En1+/+ and En2-/- and En2 expression is increased in ASD patients. This work consisted in extending the knowledge of Engrailed expression and functions. We explored the links with a telencephalic structure where it is a priori fewly expressed (hippocampus). Our results confirm En1 and En2 expression in the mature hippocampus and describe their respective expression along the development of this structure. En1 and En2 have different expression patterns during the first post-natal week as well as in the adulthood suggesting a genetic dosage of Engrailed during the development, specifically with the beginning of synaptogenesis. We also reveal that Engrailed, expressed in hippocampal neurons, is more expressed in GABA-ergic neurons, notably in their dendritic and axonal neurites. We observe that an excess of Engrailed (described in some ASD cases) increases dendritic complexity as well as plastic dendritic spine density, without affecting mature excitatory synapses. We show that En2-/- and heterozygote En1 mice have variations in dendritic spine density, which confirms that Engrailed is involved either in their formation or stabilization. Even though our experiments show no modification of synapse density with an excess of Engrailed, a mutant showing a decreased eIF4E interaction and less efficient than wild type Engrailed to increase dendritic spine density, decreases presynaptic button density and synaptic matching. Those results indicate that eIF4E interaction with Engrailed is, at least in part, responsible for its effects on spinogenesis and suggest a role of Engrailed in presynaptic button formation/stabilization. Key-role of eIF4E in translation allow to hypothesize that some of Engrailed effects we report could be translation dependent. In this sense, our results show that Engrailed is able to increase proteic synthesis in hippocampal neurons. This translation is different from the one induced by chemical LTP (LTPc): it is not altered by synthetic AβO, which are the main toxic agent when produced at abnormally high levels in Alzheimer disease. Engrailed is also able to restore defaulting translation in neurons from Alzheimer disease mice model (TG2576). As a whole, our results identify Engrailed as a novel actor in dendritic plasticity. They reveal that an excess of Engrailed during synaptogenesis can modify dendrite characteristics. This can lead to dendritic network dysfunction in a context of pathologic surexpression of Engrailed. Our observations open to new perspectives contributing to a better understanding of the relationship between Engrailed and ASD. Finally, this work lays the foundation to potentially fruitful links between Engrailed and AβOligomers signalling pathways, where modulation of protein synthesis could be a therapeutic lever in physiopathologic conditions.

The most common comorbid disorder for adolescents with autism spectrum disorder (ASD) is depression, with more severe symptoms demonstrated in those with high cognitive ability. Feelings of loneliness are associated with depression. There is a dearth of information regarding pertinent variables for loneliness of friendship quality, friendship motivation, and social skills in high ability adolescents with ASD. This study employs a multiple case study design with 10 twice-exceptional adolescent males with high cognitive ability and ASD (ages 13-9 to 18-11) to investigate these variables. Adolescent, parent, and teacher interviews were completed, transcribed, and analyzed using Consensual Qualitative Research (CQR). Results describe friendship quality for these youth, with particular contributions to current understanding of companionship, security, help, closeness and balance. Findings inform friendship motivation, as well, and etiologies of amotivation are documented. Results indicate positive and negative influences of high intelligence on interpersonal functioning, along with immaturity and symptoms of rigidity affecting friendships, as well. Pathway analyses reveal twice-exceptional youth with insecure friendships experience loneliness and introjected motivation for friendships, along with increases in peer dyadic relationships and decreases in loneliness. Those with insecure friendships and perseverative interest in peers also present with suicidal ideation and/or attempts. Future research should expand the use of individual therapies (i.e., cognitive behavioral therapy for depression) for these twice-exceptional teens, particularly in middle school, with modifications to accommodate difficulties with perseveration on negative emotions, as well as explore coping strategies of engaging with fictional characters when lonely.

Pharmacogenetics is the study of genomic-guided individualized drug prescription that plays an important role in preventing the severe adverse effects of drugs, decreasing the time and cost of therapeutic choices, and directing healthcare professionals to choose medications that are effective and safe. It is noteworthy that this approach becomes highly beneficial in patients suffering from chronic diseases or disorders, since these conditions may require multiple and long term pharmacological therapies, as in children with autism spectrum disorder (ASD). However, public acceptance is a major challenge when implementation of pharmacogenetics merges into clinical practice. The purpose of this study is a) to investigate, among small cohort group of children with ASD, several genetic variants of enzymes that influence the metabolism of commonly prescribed drugs to treat ASD and b) to inspect the knowledge of, attitude towards and future expectations with regards to pharmacogenetics among parents of children with ASD. A group of 15 school-aged participants with ASD were recruited for the study. Approximately 5 ml of venous blood was drawn for each participant to analyze the genotype of enzymes implicated in drug metabolism via pharmacogenetics testing. Thereafter, the parents of these children attended a training session to help them gain a better understanding of the pharmacogenetics results depicted in the drug panel results. A pre-training and post-training survey was conducted to assess the knowledge of, attitude towards and future expectations of pharmacogenetics among the children’s parents.

Autism Spectrum Disorder (ASD) refers to a heterogeneous neurological condition characterized by repetitive and restrictive behaviors and social communication deficits. ASD diagnoses are at a record high, at approximately 1 in 59 children according to the US Center for Disease Control. Currently, there are no available interventions that effectively treat the core symptoms of ASD. All pharmaceutical options address comorbid side effects of ASD but not core deficits and are particularly associated with negative side effects. Additionally, there are economic and geographic barriers that can prevent families of individuals with ASD from seeking or receiving effective interventions. Many of the available interventions are extremely costly, time-consuming, and age dependent. These factors, as well as others, have led to an increase in families independently utilizing complementary and alternative interventions. Due to the large amount of misinformation available on the Internet, families have become more susceptible to trying alternative forms of interventions that have not been scientifically proven as effective, and in some cases, are significantly detrimental. Thus, the need for accessible and inexpensive evidence-based nonpharmaceutical interventions is critical and must be addressed. Fortunately, recent groundbreaking research has discovered two strains of probiotics, Bacteroides fragilis and Lactobacillus reuteri, that have been shown to ameliorate behavioral and social deficits respectively, in validated ASD mouse models in a non-age-dependent manner. Probiotic intervention with a combination of these specific strains would effectively target both repetitive behaviors and social deficits, core ASD symptoms, and provide families with an accessible and inexpensive form of intervention. The mechanisms underlying the efficacy of these probiotics are thought to be associated with the gastrointestinal (GI) system and the oxytocin pathway. This study seeks to examine the necessity of accessible nonpharmaceutical interventions and to provide an effective intervention that is neither expensive or age dependent. This study also aims to provide greater insight into the pathways and systems in which these probiotics operate.

This study employed a multiple probe across settings design to evaluate the effectiveness of Power Cards, as they were originally designed by Gagnon (2001), on the conversational behaviors for two high school students diagnosed with autism spectrum disorder. Data were collected on the percentage of conversational behaviors engaged in per session, as well as the number of times the participants accessed their Power Card during conversations, and the frequency of additional questions or comments made by the participants. Results of this study indicated that Power Cards improved conversational behaviors for both participants in their first setting. While covariation occurred across untrained settings for both participants, therefore weakening the experimental control of this study, promising results were produced for Sunday practitioners and teachers.

Music therapists frequently work with clients with Autism Spectrum Disorder (ASD) who use Augmentative and Alternative Communication (AAC). The purpose of this study was to gather information on music therapists’ current experiences with AAC training as well as music therapists’ perceptions of their own communication abilities when communicating with clients who have ASD using their preferred AAC system. The researcher invited 7,279 board-certified music therapists to participate in this study via email, of which 366 completed the survey. Participants reported most often providing services to children and adolescents with ASD, and frequently using electronic AAC and electronic apps with their clients with ASD. The majority (71.2%) of participants stated that they would like additional training in the use of AAC. Of the music therapists who had participated in previous AAC training, many had received training at work or by an SLP or other certified professional. Results of this study provide information about the current practices and perceptions of board-certified music therapists working with clients with ASD.

Children with autism, by diagnostic criteria, experience a lack of age appropriate play and social skills (American Psychiatric Association, 1994). This study evaluated three typically developing peer's ability to implement Pivotal Response Training strategies during recess with a child with autism in their third grade class. A concurrent multiple probe baseline across peers design was used to assess peers ability to implement Pivotal Response Training strategies with the target child and the effects of intervention on the play and communication behavior of the target child. Generalization measures were taken in an untrained environment. Measures of social validity in the form of peer interviews and teacher questionnaire were completed. Results displayed that peers were able to use Pivotal Response Training strategies during recess with a child with autism. During post-training/intervention and follow-up sessions the child with autism engaged in higher levels of communication to peers, and slightly lower levels of communication to self. The target child also experienced a decreasing trend in levels of solitary play, an increasing trend in levels of play with peer trainers and levels of parallel play remained near baseline levels. Peers were also able to generalize these skills to an untrained environment to an extent.

This thesis presents a study to develop and explore the use of a computerized system that provided automated prompts to children with ASD during the completion of a self-care activity (handwashing). A Wizard-of-Oz experiment was implemented using an A-B experimental design. During the baseline phase (A) the child’s caregiver was asked to guide the child through handwashing, in the intervention phase (B) the system guided the child. The results showed that the system was not very successful to guide the child. He tended to get distracted very easily presenting off-task behaviour, which resulted in needing assistance from the caregiver. The data obtained showed that during the intervention phase the assistance from the caregiver consisted mostly of verbal instructions versus the hand over hand guidance observed during B phase. From the data analyses and reviewed literature some improvements and redesigns were suggested which could help develop a more automatic prompting system.

This thesis presents a study to develop and explore the use of a computerized system that provided automated prompts to children with ASD during the completion of a self-care activity (handwashing). A Wizard-of-Oz experiment was implemented using an A-B experimental design. During the baseline phase (A) the child’s caregiver was asked to guide the child through handwashing, in the intervention phase (B) the system guided the child. The results showed that the system was not very successful to guide the child. He tended to get distracted very easily presenting off-task behaviour, which resulted in needing assistance from the caregiver. The data obtained showed that during the intervention phase the assistance from the caregiver consisted mostly of verbal instructions versus the hand over hand guidance observed during B phase. From the data analyses and reviewed literature some improvements and redesigns were suggested which could help develop a more automatic prompting system.

Aquest treball és una contribució a l'estudi de diferents problemes que sorgeixen de dues àrees fortament connexes de la Teoria de Grafs: etiquetaments i descomposicions. Molts etiquetaments de grafs deuen el seu origen als presentats l'any 1967 per Rosa. Un d'aquests etiquetaments, àmpliament conegut com a etiquetament graceful, va ser definit originalment com a eina per atacar la conjectura de Ringel, la qual diu que el graf complet d'ordre 2m+1 pot ser descompost en m copies d'un arbre donat de mida m. Aquí, estudiem etiquetaments relacionats que ens donen certes aproximacions a la conjectura de Ringel, així com també a una altra conjectura de Graham i Häggkvist que, en una forma dèbil, demana la descomposició d'un graf bipartit complet per un arbre donat de mida apropiada. Les principals contribucions que hem fet en aquest tema són la prova de la darrera conjectura per grafs bipartits complets del doble de mida essent descompostos per arbres de gran creixement i un nombre primer d'arestes, i la prova del fet que cada arbre és un subarbre gran de dos arbres pels quals les dues conjectures es compleixen respectivament. Aquests resultats estan principalment basats en una aplicació del mètode polinomial d'Alon. Un altre tipus d'etiquetaments, els etiquetaments magic, també són tractats aquí. Motivats per la noció de quadrats màgics de Teoria de Nombres, en aquest tipus d'etiquetaments volem asignar nombres enters a parts del graf (vèrtexs, arestes, o vèrtexs i arestes) de manera que la suma de les etiquetes assignades a certes subestructures del graf sigui constant. Desenvolupem tècniques basades en particions de certs conjunts d'enters amb algunes condicions additives per construir etiquetaments cycle-magic, un nou tipus d'etiquetament introduït en aquest treball i que estén la noció clàssica d'etiquetament magic. Els etiquetaments magic no donen cap descomposició de grafs, però les tècniques usades per obtenir-los estan al nucli d'un altre problema de descomposició, l'ascending subgraph decomposition (ASD). Alavi, Boals, Chartrand, Erdös i Oellerman, van conjecturar l'any 1987 que tot graf té un ASD. Aquí, estudiem l'ASD per grafs bipartits, una classe de grafs per la qual la conjectura encara no ha estat provada. Donem una condició necessària i una de suficient sobre la seqüència de graus d'un estable del graf bipartit de manera que admeti un ASD en que cada factor sigui un star forest. Les tècniques utilitzades estan basades en l'existència de branca-acoloriments en multigrafs bipartits. També tractem amb el sumset partition problem, motivat per la conjectura ASD, que demana una partició de [n] de manera que la suma dels elements de cada part sigui igual a un valor prescrit. Aquí donem la millor condició possible per la versió modular del problema que ens permet provar els millors resultats ja coneguts en el cas enter per n primer. La prova està de nou basada en el mètode polinomial. / This work is a contribution to the study of various problems that arise from two strongly connected areas of the Graph Theory: graph labelings and graph decompositions. Most graph labelings trace their origins to the ones presented in 1967 by Rosa. One of these labelings, widely known as the graceful labeling, originated as a means of attacking the conjecture of Ringel, which states that the complete graph of order 2m+1 can be decomposed into m copies of a given tree of size m. Here, we study related labelings that give some approaches to Ringel's conjecture, as well as to another conjecture by Graham and Häggkvist that, in a weak form, asks for the decomposition of a complete bipartite graph by a given tree of appropriate size. Our main contributions in this topic are the proof of the latter conjecture for double sized complete bipartite graphs being decomposed by trees with large growth and prime number of edges, and the proof of the fact that every tree is a large subtree of two trees for which both conjectures hold respectively. These results are mainly based on a novel application of the so-called polynomial method by Alon. Another kind of labelings, the magic labelings, are also treated. Motivated by the notion of magic squares in Number Theory, in these type of labelings we want to assign integers to the parts of a graph (vertices, edges, or vertices and edges) in such a way that the sums of the labels assigned to certain substructures of the graph remain constant. We develop techniques based on partitions of certain sets of integers with some additive conditions to construct cycle-magic labelings, a new brand introduced in this work that extends the classical magic labelings. Magic labelings do not provide any graph decomposition, but the techniques that we use to obtain them are the core of another decomposition problem, the ascending subgraph decomposition (ASD). In 1987, was conjectured by Alavi, Boals. Chartrand, Erdös and Oellerman that every graph has an ASD. Here, we study ASD of bipartite graphs, a class of graphs for which the conjecture has not been shown to hold. We give a necessary and a sufficient condition on the one sided degree sequence of a bipartite graph in order that it admits an ASD by star forests. Here the techniques are based on the existence of edge-colorings in bipartite multigraphs. Motivated by the ASD conjecture we also deal with the sumset partition problem, which asks for a partition of [n] in such a way that the sum of the elements of each part is equal to a prescribed value. We give a best possible condition for the modular version of the sumset partition problem that allows us to prove the best known results in the integer case for n a prime. The proof is again based on the polynomial method.