There is now considerable evidence that both schizophrenia and affective disorders have their origin at least in part in events that occur during early pre- and post-natal development. In the case of schizophrenia, many observations, for example, increased risk for schizophrenia in the offspring of mothers who had influenza A during their second trimester of pregnancy and evidence for abnormal neuronal migration in the cerebral cortex of post mortem tissue from schizophrenic patients, suggest that a second trimester insult may have occurred and that this insult may have increased the risk for the development of schizophrenia in late adolescence or early adulthood. Animal studies have found that rats that undergo excitotxic damage to the ventral hippocampus on postnatal day 7 develop exaggerated sensitivity to dopamine-stimulating drugs or to stressful stimuli that becomes apparent after sexual maturity but not before, providing a neurodevelopmental model of schizophrenia. Similarly, post-weaning social isolation leads to nehanced responses to dopaminergic drgus and to stress that emerges after sexual maturity. These animal models are proving to be valuable tools to study the neurobiological mechanisms mediating the influence of early insults to the nervous system on later behavioural functins. In the case of affective disorders, although the evidence is not as strong, a number of the same observations have been made suggesting that an insult during early ontogeny may lead to the development of affective disorders later in life. For example, retrospective studies of people with affective disorders showed that they were more likely to have attained motor milestones at a later age and to have had poorer academic performance as children. There is a wealth of evidence suggesting hyperfunctioning of the hypothalamic-pituitary-adrenal (HPA) axis in affective disorders. Animal studies have shown that early matenal deprivation can lead to lasting changes in the reactivity of the HPA axis to stressful stimuli, providing another link from early experience to adult psychopathology. Continued studies of the effects of pre- and early post-natal events on the development of the nervous system and the relationships of these events to schizophrenia or affective disorder will provide new insights into the mechanisms underlying these common neuropsychiatric illnesses.

No description available.

Des variants récessifs touchant le gène PIGB, encodant une enzyme impliquée dans la biosynthèse des ancres GPI, ont récemment été décrits chez des patients présentant une déficience héritée des ancres GPI ainsi qu’une encéphalopathie épileptogène (EE), une forme d’épilepsie infantile sévère associée à des atteintes cognitives. Chez l’humain, plus de 150 protéines, dont certaines sont critiques pour la fonction neuronale, sont localisées à la membrane cellulaire grâce aux ancres GPI. Des données préliminaires du laboratoire Rossignol démontrent que la délétion embryonnaire du gène Pigb dans les interneurones GABAergiques (IN) dérivés de l’éminence ganglionnaire médiale (MGE) est suffisante pour induire des crises d’épilepsie spontanées et des déficits cognitifs chez la souris, suggérant un rôle critique de PIGB dans le développement de l’inhibition corticale. Toutefois, les mécanismes cellulaires et moléculaires sous-tendant les phénotypes cliniques associés aux délétions du gène PIGB sont inconnus. Compte tenu du rôle central joué par les molécules de guidage, dont certaines sont des protéines à ancrage GPI, lors de la migration des IN vers la plaque corticale, nous postulons que la perte sélective des ancres GPI, résultant d’une délétion conditionnelle de Pigb dans les IN, altère leur dynamique de migration, ce qui a pour conséquence de réduire leur nombre dans le cortex postnatal, menant à une désinhibition corticale et au développement de l’épilepsie. L’imagerie en temps réel d’explants cellulaires de MGE a révélé que la perte de fonction du gène Pigb dans les IN dérivés du MGE entraine un défaut de la migration tangentielle et des anomalies morphologiques se traduisant par une réduction de la densité des IN dans le cortex postnatal. Nous avons également démontré que la signalisation motogène EphA4-éphrineA2 est altérée dans les IN déficients en ancres GPI, contribuant au délai de migration observé. En somme, nos travaux ont permis de préciser les mécanismes physiopathologiques sous-tendant les EE associées à des variants pathogéniques du gène PIGB et d’approfondir notre compréhension du rôle des ancres GPI durant le neurodéveloppement et plus précisément, durant la migration des IN. / Recessive variants in the PIGB gene, encoding an enzyme involved in the biosynthesis pathway of GPI anchors, were recently described in children with an inherited GPI anchor defect and epileptic encephalopathy (EE), a neurodevelopmental disorder characterized by early-onset epilepsy with cognitive impairment. GPI anchors are critical for the membrane attachment of at least 150 human proteins, some of which are important for proper neuronal function. Preliminary data from the Rossignol group show that the embryonic deletion of Pigb in GABAergic interneurons (INs) emanating from the medial ganglionic eminence (MGE) causes spontaneous seizures and cognitive deficits in mice, suggesting a critical role of PIGB in the establishment of cortical inhibition. However, the cellular and molecular mechanisms leading to epilepsy remain unknown. Given the central role of guidance molecules, some of which are GPI-anchored proteins, during neuronal migration, we postulate that loss of GPI anchors following the conditional deletion of Pigb in MGE-derived INs disrupts chemotactic guidance and IN migration dynamics, leading to cortical disinhibition and epilepsy post-natally. Time-lapse live imaging of MGE explants revealed that the targeted deletion of Pigb impairs the tangential migration as well as the morphological development of MGE-derived INs, resulting in reduced IN densities in the postnatal cortex. We showed that the kinetic deficits are partly due to a loss of EphA4-ephrinA2 motogenic signaling in PigbcKO INs. In summary, our work helps clarify the physiopathology underlying PIGB associated-EE and deepens our understanding of the roles of GPI-anchor-related pathways in neurodevelopment and more specifically, in the migration of cortical INs.

Le gène INTS11 est une sous-unité catalytique du complexe Integrator qui joue un rôle central dans le traitement de divers ARN naissants. Récemment, des patients présentant des mutations de perte de fonction dans le gène INTS11 ont été signalés comme ayant des problèmes neurodéveloppementaux graves, des problèmes ataxiques et des retards de développement globaux. À ce jour, aucune mutation dans INTS11 n'a été liée à des maladies humaines, et aucune preuve ne soutient leur rôle dans des problèmes neurodéveloppementaux. Par conséquent, nous avons développé un modèle INTS11 knock-out (KO) F0 CRISPRant chez le poisson-zèbre pour caractériser fonctionnellement les mutations de perte de fonction de ce gène in vivo. Nos larves INTS11-KO présentent une accumulation accrue de snARN mal traités, confirmant la perturbation de la fonction du gène. De plus, les larves INTS11-KO meurent prématurément à 14 jours et présentent un phénotype comportemental aberrant, similaire à d'autres modèles génétiques de poisson-zèbre des troubles neurodéveloppementaux. Aussi, les larves INTS11-KO présentent une réduction de la taille du cerveau avec une réduction du contenu neuronal. Enfin, nos résultats d'immunomarquage ont révélé une réduction de la taille du cervelet chez les larves INTS11-KO. Dans l'ensemble, ces données soutiennent le rôle d'INTS11 dans le développement cérébral et sont cohérentes avec les retards neurodéveloppementaux décrits chez les patients présentant des mutations délétères dans ce gène. Notre étude montre comment des organismes modèles simples tels que le poisson-zèbre peuvent aider à caractériser l'étiologie génétique des troubles génétiques. Les résultats de nos recherches pourraient contribuer à des diagnostics plus précis et ouvrir la voie à la découverte de mécanismes pathogènes clés qui pourraient être exploités pour le développement de traitements pour les patients présentant des mutations dans INTS11. / The INTS11 gene is a catalytic subunit of the Integrator complex that plays a central role in processing various nascent RNAs. Recently, patients with loss-of-function mutations in the INTS11 gene have been reported to have severe neurodevelopmental issues, ataxic problems, and global developmental delays. To date, mutations in INTS11 have not been linked to human diseases, and no evidence supports their role in neurodevelopmental problems. Therefore, we developed an ints11 F0 CRISPRant knock-out (KO) model in zebrafish to functionally characterize loss-of-function mutations in this gene in vivo. Our ints11-KO larvae exhibited an increased accumulation of unprocessed snRNAs, confirming the disruption of the ints11 function. Moreover, ints11-KO larvae die prematurely by 14 days of age and display an aberrant behavioural phenotype, similar to other zebrafish genetic models of neurodevelopmental disorders. Furthermore, ints11-KO larvae show reduced brain size with reduced neuronal content. Finally, immunostaining results revealed a reduction in cerebellum size in our ints11-KO. Altogether, these data support the role of INTS11 in brain development and are consistent with the neurodevelopment delays described in patients with deleterious mutations in this gene. Our study shows how simple model organisms like zebrafish can help characterize the genetic etiology of genetic disorders. The results from our research could aid in more accurate diagnoses and open the path to unveiling key pathogenic mechanisms that could be leveraged for the development of treatment for patients with mutations in INTS11.

Preterm birth disrupts the development of the brain and other critical organs of the infant body. Since the brain is one of the last organs to finish developing during pregnancy, the risk for substantial neurological deficits increases as the gestational age decreases. One way to combat these deficits is to reconnect the preterm infant with the mother via skin-to-skin contact, also known as kangaroo care (KC). This intimate touch helps to replicate aspects of the environment that the preterm infant experienced in utero. The purpose of this literature review was to analyze the current literature to better understand the effects that KC may have on facilitating neurodevelopment of preterm infants in Neonatal Intensive Care Units (NICUs). Emphasis was placed on neurophysiologic functioning, autonomic functioning, and neurobehavioral functioning. A database search of CINAHL Plus with Full Text, PsycINFO, MEDLINE, Cochrane Central Register of Controlled Trials, and Health Source: Nursing/Academic Edition was conducted, and a total of six articles were reviewed based on their relevance and application towards this thesis. KC is a low-cost, relatively easy intervention to initiate that can have positive impacts on many aspects of preterm infant growth and maturation. There is limited research regarding the use of KC as an intervention to support neurodevelopment, especially with regards to long-term effects. Existing research supports the use of KC as an intervention to facilitate neurodevelopment in preterm infants in the NICU.

No description available.

La neuropathie sensitive et motrice héréditaire avec agénésie du corps calleux (NSMH/ACC) se traduit par une atteinte neurodégénérative sévère associée à des anomalies développementales dans le système nerveux central et du retard mental. Bien que rare dans le monde, ce désordre autosomique récessif est particulièrement fréquent dans la population Québécoise du Canada Français du fait d’un effet fondateur. L’unique étude réalisée sur la mutation québécoise du gène qui code pour le co-transporteur de potassiumchlore 3 (KCC3) a montré qu’il y a une perte de fonction de la protéine. Cependant, la maladie est également retrouvée hors du Québec et il reste encore à élucider les pathomécanismes mis en jeu. Nous avons donc séquencé les 26 exons du gène KCC3 chez des individus recrutés dans le monde entier et suspectés d’être atteints de la maladie. Nous avons ainsi identifié trois nouvelles mutations. L’étude fonctionnelle de ces mutations nous a confirmé la perte de fonction systématique des co-transporteurs mutés. Puisque l’inactivation de KCC3 se produit majoritairement via l’élimination de segments peptidiques en C-terminus, nous avons concentré notre attention sur l’identification des interactions qui s’y produisent. À l’aide d’approches double hybride, pull-down et immunomarquage, nous avons déterminé que KCC3 interagit avec la créatine kinase CK-B et que cette interaction est perturbée par les mutations tronquantes. De plus, l’utilisation d’un inhibiteur de créatine kinase inactive KCC3, ce qui démontre qu’il existe bien un lien fonctionnel et pathologique entre KCC3 et ses partenaires C-terminaux. Nous avons aussi identifié des anomalies majeures de localisation membranaire des KCC3 mutés. Que KCC3 soit tronqué ou pleine longueur, sa distribution subcellulaire est affectée dans des cellules en culture, dans les ovocytes de Xenopes et dans des échantillons de cerveau de patients. La perte d’interaction entre KCC3 et CK-B et/ou les défauts de transit intracellulaire de KCC3 sont donc les mécanismes pathologiques majeurs de la NSMH/ACC. / Heredirary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is a severe neurodegenerative disease associated with developmental anomalies in the central nervous system and mental retardation. Although rare worldwide, this autosomal-recessive disorder is frequent in the French-Canadian population of Quebec because of a founder effect. Different mutations in the gene coding for the potassiumchloride co-transporter 3 (KCC3) have been associated with the disease; however, little is known about the mechanisms leading to the inactivation of the co-transporter. We sequenced 26 exons of the KCC3 gene in individuals recruited worldwide and suspected to be affected by the disease. We identified three new mutations. The functional study of these mutations gave confirmation of a systematic loss-of-function of the mutant co-transporters. As the loss of function occurs mainly via the elimination of C-terminal peptide fragments, we focused on the identification of C-terminal interacting partners. Using different biochemical approaches, such as yeast two-hydbrid, pull-down, and immunostaining, we established that KCC3 interacts with the brain-type creatine kinase CK-B and that this interaction is disrupted by the HMSN/ACC truncation mutations. In addition, a specific creatine kinase inhibitor inactivates KCC3 and shows for the first time the functional link between KCC3 and its C-terminal partners. In addition, we found that anomalies in KCC3 transit—as seen in cultured cells, in Xenopus oocytes, and in human brain samples—is a major pathogenic mechanism that also leads to the disease manifestations.

INTRODUÇÃO: Exposição a fatores ambientais e estresse durante o período intrauterino estão associados com alterações da trajetória do neurodesenvolvimento de forma sexo-dependente. Mecanismos epigenéticos estão envolvidos a esta associação. OBJETIVOS: Analisar de acordo com a exposição ao estresse na gestação o impacto do sexo e de alterações de metilação do DNA no sangue de cordão umbilical nas medidas antropométricas do neonato. MÉTODOS: Foram recrutadas 94 gestantes e aplicados questionários de medidas exposição ao estresse e fatores de risco durante a gravidez. A coleta de sangue do cordão umbilical seguiu protocolo padronizado. Para analisar o estresse foi utilizada análise de componentes principais (ACP) dos fatores de exposição avaliados: status socioeconômico, educação, ganho de peso, índice de massa corporal pré-gravídico, presença de doença psiquiátrica, estresse psicossocial durante a gravidez. Após o ACP fizemos análise de agrupamento por K-means. As análises de metilação foram realizadas utilizando Illumina Infinium Human Methylation450 (450K) BeadChip. Os dados foram analisados pelos pacotes Minfi e ChAMP (Chip Analysis Methylation Pipeline). A partir das posições diferencialmente metiladas (PDMs) foi feito análise de enriquecimento de processos biológicos com a ferramenta WebGestalt. Para avaliar impacto do sexo e alterações de metilação no desfecho antropométrico do neonato usamos modelos de análise linear de regressão múltipla. RESULTADOS: A coorte final para a avaliação do estresse foi composta por 89 pares mãe/recém-nascidos, sendo 50 meninas e 39 meninos. A ACP mostrou que os primeiros 3 componentes explicaram 60% da variabilidade da amostra. Sendo o primeiro componente (CP1) estresse psíquico, o segundo CP estresse social e o CP3 exposição a tóxicos. O biplot dos primeiros dois componentes sugeriu a separação das mães em dois grupos, confirmados pela análise de agrupamentos. Usando o ponto de corte de p-valor < 0,01 e deltabeta-valor>5%, encontramos 110 posições PDMs entre os grupos e restringindo este valor para p-valor < 0,01 e delta beta valor > 10% encontramos 13 PDMs. Usando apenas as crianças adequadas para idade gestacional fizemos análise de metilação diferencial entre os sexos. Foram encontradas 426 PDMs. Nenhuma das 13 PDMs encontradas entre os dois grupos pertenciam ao conjunto das PDMs entre sexos. No modelo de regressão linear multivariada controlando para sexo da criança e idade da mãe não encontramos nenhuma PDM associada aos desfechos antropométricos do neonato. Na análise estratificada por grupos os sítios cg24702040 (MAP3K21), cg21550016 (PAX8) foram estatisticamente significantes para perímetro abdominal e cg18706028 (CCKBR) e cg21550016 (PAX8) foram estatisticamente significantes para índice do perímetro cefálico para a idade. Este estudo sugere que o estresse materno independente do sexo pode afetar o crescimento fetal, mediado por respostas epigenéticas em genes relacionados à resposta ao estresse, regulação negativa da via de sinalização do receptor do fator de crescimento epidérmico, biogênese da sinapse e processo apoptótico / BACKGROUND: Exposure to environmental factors and stress during the intrauterine period are associated with changes in the neurodevelopmental trajectory in a sex-dependent manner. Epigenetic mechanisms are involved in this association. OBJECTIVES: Analyze according to exposure to stress during pregnancy the impact of sex and DNA methylation alterations on umbilical cord blood in the anthropometric measurements of the neonate METHODS: A total of 94 pregnant women were recruited and questionnaires were used to measure stress exposure and risk factors during pregnancy. Umbilical cord blood collection followed a standardized protocol. In order to analyze the stress, the principal components analysis (PCA) of the exposure factors evaluated were: socioeconomic status, education, weight gain, pre-gravid body mass index, presence of psychiatric illness, and psychosocial stress during pregnancy. After the PCA we did group analysis by k-means. Methylation analyzes were performed using Illumina Infinium Human Methylation 450 (450K) BeadChip. The data were analyzed by the Minfi and ChAMP (Chip Analysis Methylation Pipeline) packages. From the differentially methylated positions (DMPs) was made analysis of enrichment of biological processes with the tool WebGestalt. To evaluate gender impact and methylation alterations in the neonatal anthropometric outcome we used multiple regression linear analysis models. RESULTS: The final cohort for the evaluation of stress was composed of 89 mother/newborn pairs, being 50 girls and 39 boys. The PCA showed that the first 3 components accounted for 60% of the variability of the sample. Being the first component (PC1) psychic stress, the second PC social stress and PC3 exposure to toxic. The biplot of the first two components suggested the separation of the mothers into two groups, confirmed by cluster analysis. Using the cutoff point of p-value < 0.01 and delta beta-value > 5%, we found 110 DMPs between the groups and restricting this value to p-value < 0.01 and delta beta-value > 10 % we found 13 DMPs. Using only children suitable for gestational age we did differential methylation analysis between genders. There were 426 DMPs found. None of the 13 DMPs found between the two groups belonged to the pool of DMPs between the sexes. In the multivariate linear regression model controlling for child sex and age of the mother we did not find any DMP associated with the anthropometric outcomes of the neonate. In group-stratified analysis the cg24702040 (MAP3K21), cg21550016 (PAX8) sites were statistically significant for abdominal perimeter and cg18706028 (CCKBR) and cg21550016 (PAX8) were statistically significant for head cephalic circumference for age. This study suggests that maternal stress independent of sex can affect fetal growth, mediated by epigenetic responses in genes related to stress response, negative regulation of the epidermal growth factor receptor signaling pathway, biogenesis of the synapse and apoptotic process

Autisme et schizophrénie sont deux troubles psychiatriques neuro-développementaux. L’étude des formes précoces de schizophrénie, fréquemment associées aux troubles du spectre de l’autisme (TSA), a suggéré un possible continuum développemental entre ces troubles. Des arguments cliniques et épidémiologiques, et issus des études en génétique moléculaire ou en imagerie cérébrale, sont progressivement venus étayer cette hypothèse. Dans ce contexte, l’étude de la cognition sociale a fait l’objet d’un intérêt particulier, des altérations étant rapportées dans les deux troubles avec toutefois des résultats contrastés, révélant autant de points communs que de différences. Les relations entre altération de la cognition sociale et charge neuro-développementale ont par ailleurs été peu explorées. A travers nos trois études, nous avons confirmé l’existence d’altérations de la cognition sociale dans les TSA et la schizophrénie. Le MASC (Movie for the Assessment of Social Cognition), épreuve mixte et originale dont nous avons validé la version française, a permis de montrer une altération globale des capacités de mentalisation plus importante dans les TSA que dans la schizophrénie. Les Triangles Animés (épreuve d’attribution d’intention reposant sur un matériel non verbal) ont permis de révéler des différences qualitatives : tandis que l’hypomentalisation est commune aux deux troubles, l’hypermentalisation apparaît plus marquée dans la schizophrénie. Par ailleurs, à travers un continuum autisme-schizophrénie, l’altération de la cognition sociale était liée à la désorganisation de la pensée et du langage, et à l’importance des signes neurologiques mineurs (marqueur de vulnérabilité neurodéveloppementale). En outre, chez les sujets avec schizophrénie, l’hypermentalisation était corrélée à la précocité d’installation du trouble. Nos résultats soulignent l’intérêt de pouvoir repérer chez des patients adultes un trouble du développement. En ce sens, nous avons présenté les premiers éléments de validation d’un autoquestionnaire de dépistage des troubles du développement, permettant en population adulte un repérage rétrospectif des signes et symptômes d’autisme présents dans l’enfance. En conclusion, nos résultats apportent des arguments en faveur du continuum autisme-schizophrénie, en montrant l’existence d’une altération de la cognition sociale, dans ces deux troubles, corrélée à la charge neuro-développementale de façon trans-nosographique. Il existe toutefois des différences qualitatives. Un sous-groupe de sujets avec schizophrénie dont le trouble a débuté précocement semble par ailleurs se dessiner, caractérisé par une tendance à hyper-mentaliser et présentant une désorganisation plus marquée. / Autism and schizophrenia are both neurodevelopmental psychiatric disorders. Research on early-onset schizophrenia, commonly associated to autism spectrum disorders (ASD), suggested a possible developmental continuum between both of these disorders. Clinical and epidemiological evidence, and research from molecular genetics or brain imaging, come to support this hypothesis. In this context, social cognition is a matter of special interest. Impairments are reported both in the two disorders, but with inconsistent results, revealing common features as well as differences. Otherwise, links between social cognition impairments and neurodevelopmental burden have been until now poorly explored. Through the contribution of our three studies, we confirmed the importance of social cognition impairment in autism and schizophrenia. The MASC test (Movie for the Assessment of Social Cognition), an original tool which was by our findings validated in a French version, revealed higher overall impairment of mentalizing capabilities in ASD than in schizophrenia. Animated Shapes (non verbal test of attribution of intentions) revealed qualitative differences: whereas hypomentalizing is common both to ASD and schizophrenia, overmentalizing seemed to be more important in schizophrenia. Furthermore, along a continuum between autism and schizophrenia, social cognition impairment was linked to thought and language disorganization, and to neurological soft signs (a marker for neurodevelopmental load). In addition, in subjects with schizophrenia, overmentalizing was correlated to the precocity of onset of the disease. Altogether, our results highlight the need to screen developmental feature in adulthood. In that way, we presented preliminary results in order to validate a developmental disorders screening self-rated questionnaire. As a conclusion, our results bring evidence in favour of a hypothesis of a continuum between autism and schizophrenia, showing a social cognition impairment in both disorders, correlated to the neurodevelopmental load existing in both of them in a transnosographic way. We contributed to emphasize the sub-group of subjects with schizophrenia with early-onset of disease, characterized by a tendency to overmentalizing and presenting a marked disorganization. Our work provides avenue to further studies, integrating neuroimaging and genetic data, that will help to advance in a deeper comprehension of the pathophysiology of autism and schizophrenia. Furthermore, we used and validated in this work promising tools to improve finely psychopathological evaluation and differential diagnosis in adults suffering from autism and from schizophrenia.

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.