Autism or autism spectrum disorder (ASD) is a multifaceted neurological condition that impairs social interaction, communication and behaviour. The current increase in the prevalence of ASD is alarming. A large population of parents is left searching for answers regarding their child’s developmental delays. Once their child has been diagnosed, they have to deal with the challenge of raising such a child. Parenting a child with ASD is particularly challenging for mothers as it has been reported that they struggle with poor health and wellbeing as well as high stress levels. Literature has also shown that the maternal interaction style impacts the prognosis for the child’s development, again highlighting the importance of the mother’s wellbeing. Several studies refer to the severe impact of ASD on the family as a unit, yet the unique challenges that mothers face are often overlooked. To address the wellbeing of these mothers, it is necessary to understand their experiences of their child’s diagnosis with ASD. This qualitative phenomenological study explored and described mothers’ experiences of their child’s diagnosis with ASD by using the Process-Person-Context-Time model from Bronfenbrenner’s bioecological theory as a framework. Unstructured interviews with seven mothers were conducted, voice recorded and transcribed. Data was analysed using thematic content analysis. Findings revealed four interrelated themes: 1) the mother’s experience of the interactions and relationships within her immediate family (Proximal Process), 2) the mother’s experience of her internal and external characteristics and resources (Person), 3) the mother’s experience of her environment (Context), and 4) the mother’s experience of the journey through time (Time). Bronfenbrenner’s theory in its matured form also proved to be of value in understanding these mothers’ daily lives and challenges. The key findings provide valuable insight that may inform professionals who develop support programmes aimed at mothers with ASD children or that may guide such professionals’ therapeutic interventions with mothers with ASD children. / MSW, North-West University, Potchefstroom Campus, 2015

A neotenia é um importante processo biológico-evolutivo que conserva traços fenotípicos do jovem no indivíduo adulto. A neotenia modifica a velocidade típica da ontogênese das características morfológicas compartilhadas pelos ancestrais. Essas mudanças podem representar oportunidades de mudanças fenotípicas dramáticas com poucas alterações genéticas, possibilitando alterações de estados especializados. O etólogo Konrad Lorenz reconheceu características neotênicas em humanos e algumas espécies de mamíferos na fórmula estrutural do corpo (principalmente da face) típica de infantes. Essa fórmula corpórea foi batizada por Lorenz de Kindchenschema. Os humanos típicos respondem quando observam traços infantis ativando uma resposta chamada de Efeito Kindchenschema (EK). Neste efeito verifica-se uma diminuição da agressividade, estimulação do cuidado parental e engajamento social. São raros os trabalhos de escaneamento do olhar em portadores de disfunções do neurodesenvolvimento, como a Síndrome de Williams (SW) e o Transtorno do Espectro Autista (TEA). O presente trabalho é o primeiro na literatura a investigar o escaneamento do olhar em portadores de SW e TEA usando estímulos faciais neotênicos de humanos e animais. Na presente investigação foram estudados 21 portadores de SW e 25 portadores de TEA, o grupo controle (GC) contou com 33 participantes. Encontramos uma correspondência entre os resultados declarados do estímulo preferido e o tempo de fixação. Os resultados mostraram que todos os participantes fixaram mais a região dos olhos de humanos e animais, sendo que o GC fixou mais tempo do que os portadores de SW e TEA. Foi possível separar usando o tempo de fixação nos olhos e HeatMaps os três grupos investigados. É viável a produção de um exame clínico auxiliar rápido e não-invasivo para indivíduos com suspeita de uma disfunção do neurodesenvolvimento. Talvez a região do nariz e boca sejam menos importantes e as orelhas mais importantes do que pensávamos nos estímulos neotênicos. Os estímulos mais neotênicos de infantes humanos e animais produziram um padrão semelhantes do tempo de fixação nos três grupos estudados. Esses resultados demonstram que portadores de SW e TEA respondem positivamente a estímulos faciais neotênicos. Sugerimos que as novas investigações na área incorporem também como variáveis faciais as orelhas, cor do cabelo e olhos, e simetria facial / Neoteny is an important biological-evolutionary process that retains phenotypic traits of the young in the adult individual of a species. Neoteny modifies the typical ontogeny velocity of the morphological characteristics shared with the ancestors. These changes may represent opportunities for dramatic phenotype modifications with few genetic changes, allowing for alterations in specialized states. The ethologist Konrad Lorenz has recognized neotenic characteristics in humans and some species of mammals in the structural formula of the body (mainly of the face) typical of infants. This body formula was named by Lorenz Kindchenschema. Typical humans respond when they observe infant traits by activating a response called the Kindchenschema Effect (KE). In this effect, there is a decrease in aggressiveness, stimulation of parental care and social engagement. There is a paucity of eye scanning in individuals with neurodevelopmental disorders such as Williams Syndrome (WS) and Autistic Spectrum Disorder (ASD). The present work is the first in the literature to investigate the eye scanning in WS and ASD patients using neotenic facial stimuli of humans and animals. In the present investigation, 21 WS and 25 ASD participants were studied. The control group (CG) had 33 participants. We found a correspondence between the stated results of the preferred stimulus and the fixation time. The results showed that all the participants fixed more the region of the eyes of humans and animals, and the CG fixed more time than the WS and ASD participants. It was possible to distinguish, using the fixation time in the eyes and Heat Maps, the three groups. The production of a rapid and non-invasive auxiliary clinical examination is feasible for individuals suspected in presenting a neurodevelopmental dysfunction. Perhaps the nose and mouth areas are less important, and the ears are more important than previously considered with respect. The more neotenic stimuli of human and animal infants produced a similar pattern of fixation time in the three groups studied. This may represent a greater adaptive value than we thought of those with WS and ASD. We suggest that the new investigations can also incorporate facial variables as ears, hair color and eyes, and facial symmetry

Transtorno do espectro autista (TEA) é um quadro complexo do neurodesenvolvimento associado com elevado prejuízo funcional, onde os pacientes apresentam alterações comportamentais, déficit de comunicação e problemas de sociabilização. A incidência do TEA é muito elevada e vem crescendo constantemente nos últimos anos. Atualmente a prevalência é de 1 em cada 50 crianças nos EUA, sendo os meninos mais afetados que as meninas (4:1). O diagnóstico dos pacientes com TEA é feito clinicamente e ocorre geralmente com a idade de aproximadamente três anos, idade que os sintomas ficam mais evidentes. As causas biológicas e genéticas do autismo vem sendo estudadas em modelos animais e em material biológico humano, como sangue (genéticas) e cérebro post-mortem. Apesar de valiosos, esses modelos não permitem estudos das células neurais humanas em funcionamento. A geração de células neurais funcionais a partir das células previamente reprogramadas mudou esse cenário e abriu portas para gerar modelos celulares e estudar as doenças in vitro. Esse trabalho teve como objetivo modelar o TEA in vitro, a partir de neurônios e astrócitos derivados de células-tronco pluripotentes induzidas obtidas a partir das células-tronco de dente decíduo esfoliado (SHED) de pacientes com transtorno autista. Em nossos resultados observamos que neurônios autistas apresentam uma significativa diminuição na expressão de genes sinápticos quando comparados com neurônios não-autistas (controle). Além disso, ensaios funcionais de eletrofisiologia revelaram que neurônios autistas têm um número menor de picos de estimulação (spikes) por segundo, indicando neurônios possivelmente menos ativos. Em tempo, experimentos de co-cultura de neurônios e astrócitos revelaram que astrócitos autistas podem interferir na maturação e complexidade morfológica dos neurônios controle, e o inverso também foi observado, onde astrócitos de controles podem resgatar o fenótipo de neurônios autistas, sendo que um aumento significativo no nível de marcadores sinápticos, mudanças na morfologia com neurônios de pacientes mais maduros e complexos foi observado quando cultivados sobre astrócitos controles. Nossos dados indicam que os astrócitos influenciam na maturação, na complexidade e funcionalidade dos neurônios, mostrados aqui pela primeira vez para o autismo idiopático. Além disso, com este trabalho podemos afirmar que é possível modelar o autismo idiopático in vitro e estudar formas de resgate fenotípico das células afetadas na patologia visando futuras terapias para esses pacientes. A tecnologia das células reprogramadas e modelagem de doenças abre portas para novas descobertas no campo do autismo / Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by qualitative impairment communication, social interaction and restricted and repetitive patterns of behavior. The prevalence of 1 in every 50 children in The United States has been reported with a tendency to increase in recent years. Patient ASD diagnosis typically occurs by the age of 3 years and affects more boys than girls (4:1). The biological and genetic causes of autism has been studied in animal models, in human biological material such as blood and in post-mortem brain tissues. Although valuable, these models do not allow study of living human neural cells. The generation of functional neural cells from reprogrammed cells previously changed this scenario and opened doors to generate cellular models in vitro and to study diseases as autism. This study aimed to model ASD in vitro to study neurons and astrocytes derived from induced pluripotent stem cells from mesenchymal stem cells from dental pulp (SHED) from patients with idiopathic autism. In our results we found that neurons derived from patients with ASD show a significant decrease in synaptic genes compared with controls. Functional electrophysiology tests were performed and we were able to observe a smaller number of spike per second in neurons derived from patients, indicating that neurons from ASD patients has less activity than control neurons. In our co-culture assay between neurons and astrocytes we observed that astrocytes derived from patients may interfere in the maturation and morphological complexity of neurons derived from controls. On the other hand, when we grow ASD neurons on astrocytes from controls we can observe a significant increase in the level of synaptic markers, changes in morphology where we observe more mature and complex neurons. These data indicate that astrocytes influence in the maturity, complexity and functionality of neurons, data never shown before for ASD patients. With these results we can say that it is possible to model idiopathic autism in vitro. The iPSC technology and disease modeling opens doors to new discoveries and therapies for ASD patients

O Transtorno do Espectro Autista (TEA), segundo o DSM-5, se enquadra nos Transtornos do Desenvolvimento e é caracterizado por uma díade comportamental: 1) prejuízos na comunicação e interação social e 2) comportamentos repetitivos ou estereotipados. Apesar da etiologia do TEA ser desconhecida, tanto fatores genéticos quanto ambientais já foram associados à desordem, incluindo a utilização de ácido valproico (VPA) durante a gestação. Observando essa relação importante, desenvolveu-se um modelo animal de autismo induzido pela exposição pré-natal ao VPA, o qual já foi amplamente validado em aspectos comportamentais e moleculares. No primeiro capítulo desta tese, utilizamos o modelo animal de autismo obtido através de uma única injeção intraperitoneal de VPA (600mg/kg) no dia E12,5 nas ratas Wistar prenhes e testamos um tratamento pré-natal com resveratrol (RSV), através de injeções subcutâneas (3,6 mg/Kg) administradas nas ratas prenhes nos dias E6,5-E18,5. O tratamento pré-natal com RSV demonstrou ser capaz de prevenir alterações na sociabilidade recíproca, porém não teve impacto nos prejuízos na memória olfativa e comportamentos repetitivos induzidos pelo VPA. No que se refere aos dados de microRNA (miRNA), RSV foi capaz de prevenir a alteração na expressão de miR134-5p, o qual também se observou alterado em pacientes com TEA, juntamente com o miR138-5p, ambos com alvos associados à modulação do citoesqueleto na estrutura de espinhos dendríticos. Em conjunto, esses resultados demonstram que o RSV altera vias importantes no modelo, possivelmente através das suas características antioxidantes e anti-inflamatórias, as quais contrapõem os aspectos inflamatórios do VPA. Este trabalho permitiu o aprimoramento e melhor conhecimento da técnica de RT-qPCR para análise de miRNA, sendo tema do segundo capítulo da presente tese, reunindo diferentes estratégias que auxiliaram a superar potenciais problemas e interferentes no uso dessa técnica. Finalmente, no terceiro capítulo, utilizamos o modelo VPA para avaliar o efeito do tratamento pós-natal com suramina, através de uma única injeção subcutânea (20 mg/kg) administrada nos filhotes machos na idade P30. Este tratamento foi capaz de reverter alterações de sociabilidade, novidade social e comportamento do tipo ansioso, enquanto os prejuízos na sociabilidade recíproca, comportamento exploratório, estereotipia e processamento sensorial não foram revertidos por esse tratamento. Nos dados moleculares, a suramina não foi capaz de reverter o aumento de expressão nos receptores purinérgicos P2X4 (hipocampo e córtex pré-frontal medial) e P2Y2 (hipocampo), porém reverteu o aumento de IL-6 promovido pelo VPA. Assim, possivelmente a modulação comportamental associada à suramina parece não estar associada a interações específicas nos receptores purinérgicos, mas sim com uma modificação neuroimune através da interleucina pró-inflamatória IL-6, demonstrando a importância do sistema imunológico na fisiopatologia do TEA. De forma geral, a tese contribuiu para elucidar mecanismos envolvidos no desenvolvimento das características do tipo autista, demonstrando o papel relevante das alterações neuroimunes e da modulação de alvos por miRNA, as quais, em conjunto, podem contribuir para o desenvolvimento de métodos diagnósticos e adequação de estratégias farmacológicas voltados ao TEA. Palavras-chave: Comportamento animal, microRNA, neuroimune, PCR, resveratrol, sistema purinérgico, suramina, transtorno do espectro autista. / According to DSM-5, Autism Spectrum Disorder (ASD) is a developmental disorder characterized by a behavioral dyad: 1) deficits in communication and social interaction, and 2) repetitive and stereotyped behaviors. Although the etiology of ASD is still unknown, both genetic and environmental factors have been associated with the disorder, including the use of valproic acid (VPA) during gestation. Observing this important relationship, an animal model of autism induced by prenatal exposure to VPA was developed, which has already been widely validated in behavioral and molecular aspects. In the first chapter of this thesis, we used the animal model obtained through a single intraperitoneal injection of VPA (600 mg/kg) at E12.5 in pregnant Wistar rats and tested a prenatal treatment with resveratrol (RSV) by subcutaneous injections (3.6 mg/kg) administered in the pregnant rats at E6.5 to E18.5. The prenatal treatment with RSV was able to prevent changes in the reciprocal sociability, but had no impact on the deficits in olfactory memory and repetitive behavior induced by VPA. Regarding the microRNA (miRNA) data, RSV treatment was able to prevent the alteration in the expression of miR134-5p, which also was altered in ASD patients along with miR138-5p, both with targets associated with cytoskeletal modulation in the structure of dendritic spines. Taken together, these results demonstrate that RSV alters important pathways in the model, possibly through its antioxidant and anti-inflammatory properties, which counteract the inflammatory aspects of VPA. This work allowed the improvement and better knowledge of the RT-qPCR technique for miRNA analysis, which was the theme of the second chapter of this thesis, combining different strategies to overcome potential problems and interferences in this methodology Finally, in the third chapter we used the same animal model to evaluate the effect of postnatal treatment with suramin after a single subcutaneous injection (20 mg/kg) administered to male pups at P30. This treatment was able to revert VPA-induced deficits in sociability, social novelty, and anxiety-like behavior, whilst present no effect on impairments in reciprocal sociability, exploratory behavior, repetitive behavior and sensory processing. In the molecular data, suramin was not able to reverse the increase of expression in the purinergic receptors P2X4 (hippocampus and medial prefrontal cortex) and P2Y2 (hippocampus), but reversed the VPA-induced increase of proinflammatory interleukin IL-6. Thus, behavioral modulation associated with suramin appears to be related not with specific interactions in purinergic receptors, but with a neuroimmune modification through the IL-6, indicating the importance of the immune system in the ASD pathophysiology. In general, the thesis contributed to elucidate the mechanisms involved in the development of autistic-like features, demonstrating the relevant role of neuroimmune alterations and the modulation of targets by miRNA, which, together, may contribute to the development of diagnostic methods and improvement of pharmacological strategies related to ASD.

A neotenia é um importante processo biológico-evolutivo que conserva traços fenotípicos do jovem no indivíduo adulto. A neotenia modifica a velocidade típica da ontogênese das características morfológicas compartilhadas pelos ancestrais. Essas mudanças podem representar oportunidades de mudanças fenotípicas dramáticas com poucas alterações genéticas, possibilitando alterações de estados especializados. O etólogo Konrad Lorenz reconheceu características neotênicas em humanos e algumas espécies de mamíferos na fórmula estrutural do corpo (principalmente da face) típica de infantes. Essa fórmula corpórea foi batizada por Lorenz de Kindchenschema. Os humanos típicos respondem quando observam traços infantis ativando uma resposta chamada de Efeito Kindchenschema (EK). Neste efeito verifica-se uma diminuição da agressividade, estimulação do cuidado parental e engajamento social. São raros os trabalhos de escaneamento do olhar em portadores de disfunções do neurodesenvolvimento, como a Síndrome de Williams (SW) e o Transtorno do Espectro Autista (TEA). O presente trabalho é o primeiro na literatura a investigar o escaneamento do olhar em portadores de SW e TEA usando estímulos faciais neotênicos de humanos e animais. Na presente investigação foram estudados 21 portadores de SW e 25 portadores de TEA, o grupo controle (GC) contou com 33 participantes. Encontramos uma correspondência entre os resultados declarados do estímulo preferido e o tempo de fixação. Os resultados mostraram que todos os participantes fixaram mais a região dos olhos de humanos e animais, sendo que o GC fixou mais tempo do que os portadores de SW e TEA. Foi possível separar usando o tempo de fixação nos olhos e HeatMaps os três grupos investigados. É viável a produção de um exame clínico auxiliar rápido e não-invasivo para indivíduos com suspeita de uma disfunção do neurodesenvolvimento. Talvez a região do nariz e boca sejam menos importantes e as orelhas mais importantes do que pensávamos nos estímulos neotênicos. Os estímulos mais neotênicos de infantes humanos e animais produziram um padrão semelhantes do tempo de fixação nos três grupos estudados. Esses resultados demonstram que portadores de SW e TEA respondem positivamente a estímulos faciais neotênicos. Sugerimos que as novas investigações na área incorporem também como variáveis faciais as orelhas, cor do cabelo e olhos, e simetria facial / Neoteny is an important biological-evolutionary process that retains phenotypic traits of the young in the adult individual of a species. Neoteny modifies the typical ontogeny velocity of the morphological characteristics shared with the ancestors. These changes may represent opportunities for dramatic phenotype modifications with few genetic changes, allowing for alterations in specialized states. The ethologist Konrad Lorenz has recognized neotenic characteristics in humans and some species of mammals in the structural formula of the body (mainly of the face) typical of infants. This body formula was named by Lorenz Kindchenschema. Typical humans respond when they observe infant traits by activating a response called the Kindchenschema Effect (KE). In this effect, there is a decrease in aggressiveness, stimulation of parental care and social engagement. There is a paucity of eye scanning in individuals with neurodevelopmental disorders such as Williams Syndrome (WS) and Autistic Spectrum Disorder (ASD). The present work is the first in the literature to investigate the eye scanning in WS and ASD patients using neotenic facial stimuli of humans and animals. In the present investigation, 21 WS and 25 ASD participants were studied. The control group (CG) had 33 participants. We found a correspondence between the stated results of the preferred stimulus and the fixation time. The results showed that all the participants fixed more the region of the eyes of humans and animals, and the CG fixed more time than the WS and ASD participants. It was possible to distinguish, using the fixation time in the eyes and Heat Maps, the three groups. The production of a rapid and non-invasive auxiliary clinical examination is feasible for individuals suspected in presenting a neurodevelopmental dysfunction. Perhaps the nose and mouth areas are less important, and the ears are more important than previously considered with respect. The more neotenic stimuli of human and animal infants produced a similar pattern of fixation time in the three groups studied. This may represent a greater adaptive value than we thought of those with WS and ASD. We suggest that the new investigations can also incorporate facial variables as ears, hair color and eyes, and facial symmetry

Methods for Teaching Students with Autism Spectrum Disorders is the most comprehensive text available, aimed at helping pre-service and in-service teachers and related service professionals understand the importance of evidence-based practices in the education of learners with Autism Spectrum Disorders (ASD) from a family and longitudinal learning perspective. With its emphasis on the theme of family and professional partnerships and collaboration and consultation, the book includes learning aids such as suggested print and web-based resources, graphic organizers, and points for reflection; child and family vignettes, “Consider This” features, and examples of exemplary programs and practices; and the most up-to-date information and latest trends in the field. / https://dc.etsu.edu/etsu_books/1122/thumbnail.jpg

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The after-high-school outcomes for individuals with autism spectrum disorder (ASD) and their families are less than desirable. The current study employed an exploratory sequential mixed methods design in order to enhance understanding of the family adaptation process during transition. First, a qualitative study was conducted in order to understand the stressors, external and internal support, coping strategies, and family adaptation outcomes during transition, from a parent’s perspective, using the ABCX model. Thirteen parents of adolescents and young adults with ASD were interviewed. These parents reported a continually high level of stress due to normative strains and ASD-related demands. They clearly described the tangible, emotional, informational, and internal resources both received and needed. Parents, as active agents in their children’s lives, have their own views towards transition, philosophy, and ways of coping. Even though many of them reported negative experiences, these parents also found new meanings and happiness in their lives. Based on the literature review and the qualitative results, a quantitative study was then developed, which applied the ABCX model to understand the predictors of good parent transition outcomes and investigate the mediating mechanism between stressors and parent transition outcomes. At the indicator level, autism severity, mental health crisis/challenging behaviors, filial obligation, general social support, transition planning quality, parent-teacher alliance, parenting efficacy, problem-focused coping, avoidance-focused coping, and optimism were important predictors of the four benchmarks of parents’ outcomes (i.e., parents’ burden, parents’ transition experience, parents’ subjective health, and family quality of life). At the structural level, optimism, emotion-coping strategies, and resources mediated the relationships between stressors and parents’ outcomes. Research and practical applications are discussed. Findings across the two studies led to identification of key factors that influence the outcomes of parents of adolescents and young adults with ASD, as well as an understanding of the complex relationships among the predictors. The results build upon existing empirical and theoretical work related to the transition of families of adolescents and young adults with ASD. Recommendations for future research and clinical practices are discussed.

The purpose of this study was to teach four preschool children with autism spectrum disorder (ASD) to wash their hands independently using a video modeling-based intervention package. A research questions was asked: Is there a functional relation between a video modeling-based intervention package and increases in level and trend for washing hands independently? A multiple probe across participants design was used to answer this question. Results indicated that the intervention package had functional relation with the increase in level and trend of the three participants’ performance in washing hands. The intervention package of video modeling and least-to-most prompting was found to be effective to teach the participants the skills taught.

Du fondamental à la clinique, cette thèse a été construite autour d’un seul mot clefs : KCC2, grâce à plusieurs projets collaboratifs. Ce co-transporteur d’ion est une molécule à plusieurs facettes dont la multiplicité des rôles et ses implications dans diverses pathologies font d’elle un élément clef de l’organisme vivant. En plus des études phylogénétiques et thérapeutiques effectuées au cours de cette période, mon principal travail a été de déterminer le rôle physio-pathologiques in vitro et in vivo d’un mécanisme de régulation post-traductionnelle de KCC2. Nous avons dans un premier temps montré que la déphosphorylation des Thréonines (Thr) 906 et 1007 in vitro était un puissant activateur de la protéine. En effet, nous avons montré que l’état de phosphorylation des sites dicté par la voie Wnk-Spak/OSR1 était impliqué dans le niveau d’expression en surface de la protéine. Par la suite, nous avons pu révéler que les souris porteuses d’une mutation phospho-mimétique Glu906 et Glu1007 “(KCC2E/+)” sur un allèle de la protéine, présentaient un décalage de l’émergence de la force inhibitrice GABAergique, une altération de la balance excitation/inhibition, ainsi qu’une augmentation de la susceptibilité à générer des crises. De plus, ces même souris développent des troubles de la communication chez le jeune ainsi qu’un défaut de sociabilité chez l’adulte, deux symptômes clefs des TSA. Ces résultats suggèrent que la régulation post-traductionnelle est un mécanisme physio-pathologique clef de la protéine. / From basic to clinical aspects, this thesis comprises different collaborative projects focusing on KCC2. KCC2 is a complex protein with multiple roles and implications in various pathologies that makes this molecule a key element of living organisms. In addition to the phylogenetic and therapeutic studies performed during this period, my main work has been to determine the in vitro and in vivo physio-pathological role of a KCC2 post-translational regulatory mechanism. We first showed in vitro that dephosphorylation of Threonines (Thr) 906 and 1007 was a potent activator of the protein. We have shown that phosphorylation state by the Wnk-Spak/OSR1 pathway of these two residues is implicated in the level surface expression of KCC2. Subsequently we have revealed that mice carrying in one allele a phospho-mimetic mutations Glu906 and Glu1007 “(KCC2E/+)”, preventing the developmental dephosphorylation at these sites, exhibited a delayed onset of fast synaptic GABA inhibition, a decreased ratio of spontaneous GABA- to glutamate-driven post-synaptic responses, and a significantly reduced flurothyl-induced seizure threshold. Furthermore, KCC2E/+ pups and adult mice, respectively, exhibited impaired communication and sociability, classic ASD phenotypes. These results suggest that post-translational regulation is a key physio-pathological mechanism of KCC2.