Williams-Beuren Syndrome (WBS) is an autosomal dominant neurodevelopmental disorder caused by hemizygous deletion of a 1.5 Mb region on chromosome 7q11.23. Symptoms are numerous and include behavioural and cognitive components. One of the deleted genes, GTF2IRD1, a putative transcription factor, has been implicated in the neurological features of WBS by studying patients with atypical deletions of 7q11.23. Gtf2ird1-targeted mice have features consistent with the WBS phenotype, namely reduced innate fear and increased sociability. To identify neural targets of GTF2IRD1, microarray analyses were performed comparing gene expression in whole brains of Gtf2ird1-/- and wildtype (WT) mice at embryonic day 15.5 and at birth. Overall, the changes in gene expression in the mutant mice were not striking, with most falling in the range of 0.3 to 2 fold. qRT-PCR was used to verify the expression levels of candidate genes and examination of verified genes revealed that most were located on chromosome 5, within 50 Mb of Gtf2ird1. Expression of these candidate genes in Gtf2ird1-/- mice was found to be the same as in WT 129S1/SvImJ mice, indicating the differences were the result of flanking chromosomal material from the, 129-derived, R1 ES cells from which the Gtf2ird1-/- mice were generated, and that expression differences were unrelated to Gtf2ird1 dosage. Further analysis found that while many genes showed decreased expression using primers targeting the 3’ UTR, expression of upstream exons was not affected. Transcripts using alternative polyadenylation sites were identified using 3’ RACE, and qRT-PCR showed that expression of different 3’ UTR isoforms can occur in a strain specific manner. Expression analysis of previously identified GTF2IRD1 targets also failed to demonstrate an in vivo effect. In summary, I was unable to find any in vivo neuronal targets of this putative transcription factor, despite its robust expression in the developing rodent brain.

Williams-Beuren Syndrome (WBS) is an autosomal dominant neurodevelopmental disorder caused by hemizygous deletion of a 1.5 Mb region on chromosome 7q11.23. Symptoms are numerous and include behavioural and cognitive components. One of the deleted genes, GTF2IRD1, a putative transcription factor, has been implicated in the neurological features of WBS by studying patients with atypical deletions of 7q11.23. Gtf2ird1-targeted mice have features consistent with the WBS phenotype, namely reduced innate fear and increased sociability. To identify neural targets of GTF2IRD1, microarray analyses were performed comparing gene expression in whole brains of Gtf2ird1-/- and wildtype (WT) mice at embryonic day 15.5 and at birth. Overall, the changes in gene expression in the mutant mice were not striking, with most falling in the range of 0.3 to 2 fold. qRT-PCR was used to verify the expression levels of candidate genes and examination of verified genes revealed that most were located on chromosome 5, within 50 Mb of Gtf2ird1. Expression of these candidate genes in Gtf2ird1-/- mice was found to be the same as in WT 129S1/SvImJ mice, indicating the differences were the result of flanking chromosomal material from the, 129-derived, R1 ES cells from which the Gtf2ird1-/- mice were generated, and that expression differences were unrelated to Gtf2ird1 dosage. Further analysis found that while many genes showed decreased expression using primers targeting the 3’ UTR, expression of upstream exons was not affected. Transcripts using alternative polyadenylation sites were identified using 3’ RACE, and qRT-PCR showed that expression of different 3’ UTR isoforms can occur in a strain specific manner. Expression analysis of previously identified GTF2IRD1 targets also failed to demonstrate an in vivo effect. In summary, I was unable to find any in vivo neuronal targets of this putative transcription factor, despite its robust expression in the developing rodent brain.

Duplication and deletion of a common interval spanning 26 genes on chromosome 7q11.23 cause Dup7q11.23 Syndrome and Williams-Beuren Syndrome, neurodevelopmental disorders with contrasting anxiety phenotypes. The General Transcription Factor 2 I (GTF2I) gene has been implicated in separation anxiety, common in people with Dup7q11.23, and we studied the effects of commonly used anxiolytics on maternal separation-induced USV in mouse models with copy number changes in Gtf2i. Subcutaneous injection of saline affected both USV production and plasma corticosterone levels in a Gtf2i gene-dosage dependent manner. Drugs acting on the glutamate receptors were most effective at attenuating USVs in all genotypes, compared to GABAergic and serotonergic modulators. Brain c-fos expression after separation was reduced by a GABAA agonist, but not a glutamate antagonist. Collectively, these results suggest a potential difference in pain sensitivity based on Gtf2i copy number and implicate the glutamatergic and GABAergic systems in anxiety phenotypes in these two disorders.

Duplication and deletion of a common interval spanning 26 genes on chromosome 7q11.23 cause Dup7q11.23 Syndrome and Williams-Beuren Syndrome, neurodevelopmental disorders with contrasting anxiety phenotypes. The General Transcription Factor 2 I (GTF2I) gene has been implicated in separation anxiety, common in people with Dup7q11.23, and we studied the effects of commonly used anxiolytics on maternal separation-induced USV in mouse models with copy number changes in Gtf2i. Subcutaneous injection of saline affected both USV production and plasma corticosterone levels in a Gtf2i gene-dosage dependent manner. Drugs acting on the glutamate receptors were most effective at attenuating USVs in all genotypes, compared to GABAergic and serotonergic modulators. Brain c-fos expression after separation was reduced by a GABAA agonist, but not a glutamate antagonist. Collectively, these results suggest a potential difference in pain sensitivity based on Gtf2i copy number and implicate the glutamatergic and GABAergic systems in anxiety phenotypes in these two disorders.

Les visages fournissent à l'observateur un ensemble d'informations physiques, émotionnelles et sociales qui déterminent la manière dont les gens interagissent entre eux. Grâce aux cette informations, un humain peut se faire rapidement une première impression. La capacité de former des jugements de nature sociale est au centre de ce travail de thèse ainsi qu'à la manière dont la fiabilité d'autrui peut-être détectée spontanément à partir d'un visage. J'ai employé des techniques de suivi du mouvement oculaire, d'électrophysiologie (EEG) et comportementales. Le but de l'étude 1 visait à déterminer si la capacité d'évaluer la confiance est universelle. J'ai teste si les singes peuvent montrer une préférence spontanée envers des visages humains inspirant confiance, comme il l'a été observé chez les humains. Chez les deux espèces le temps de regard étais supérieur pour les visages inspirant confiance par rapport à ceux n'inspirant pas confiance. Un autre ensemble d'études s'intéressait au syndrome de Williams-Beuren (WS). La pathologie dont une des caractéristiques est un comportement d'appétence sociale a été utilisée comme modèle neurobiologique humain afin d'étudier la capacité à détecter les informations sociales du visage. Les patients WS sont-ils capables de détecter la confiance à partir d'un visage? Comment les patients WS se représentent un visage qui inspire confiance? J'ai observé que les patients WS regardent moins longtemps les visages qui inspirent confiance, suggérant qu'ils ont une tendance à davantage faire confiance à tout le monde. Nos résultats démontrent aussi qu'en comparaison à un groupe sain, ils ne présentent pas une image stéréotypique d'un visage qui inspire confiance. Dans une dernière étude, j'ai cherché à savoir si les sources neuronales éléctrophysiologiques, en particulier dans les régions du sulcus temporal supérieur (240ms), pouvaient expliquer leur comportement. J'ai observé que l'activité de la source était modulée de manière significative par rapport à la proximité des yeux, comme dans le groupe control. Les résultats suggèrent la présence d'une voie rapide dans le cerveau qui joue le rôle fondamental de moduler les comportements d'approche et d'évitement et que cette voie peut être altérée chez des patients caractérisés par un comportement d'appétence sociale / Faces provide a complex set of physical, emotional and social information to the observer that determines how people will interact with others. From facial information, human subjects can form rapid, first impression judgments. The ability to create social judgments from faces is the core topic of this work. This thesis will focus on how social information and trust is spontaneously detected from faces. In my studies I used eye tracking procedure, electrophysiology (EEG) and behavioral measures. In a first experiment, I investigated the evolutionary origin of trustworthiness detection testing whether monkeys (Macaca Mulatta and Fascicularis) have a spontaneous preference towards trustworthy human faces, thus suggesting a capacity to detect facial cues similar to those used by humans. Using a preference visual paradigm we observed that both species spent more time looking at trustworthy faces than untrustworthy ones. I further conducted three studies with patients affected by Williams-Beuren syndrome (WS). This pathology can be considered a neurobiological human model for the overexpressed social behavior. Are Williams-syndrome patients able to detect trustworthiness from faces? How WS patients form the representation of trustable faces ? Using a preference visual paradigm I observed that WS patients looked less the trustworthy faces compared to control group. This implicit behavior supports patients’ tendency to trust everybody. In a second experiment using reverse correlation paradigm - the procedure pushes subjects to select from noise the facial features that they believe are important for a specific judgment – I found that at group level patients did not show a stereotypical image of trustworthy faces compared to healthy controls. In a final study I investigate whether electrophysiological brain sources, with particular attention to the source localized in the superior temporal sulcus, could explain patients’ behaviour. I found that the activity of a source localized in the STS at 240ms was significantly modulated by eye proximity as in the control group. Overall the results of this work suggests the presence of a fast route in the brain that plays the fundamental role of modulating approach/avoidance behavior. This route may be altered in patients characterized by an overexpressed social behavior

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

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

Genomic rearrangements, particularly deletions and duplications, are known to cause many genetic disorders. The chromosome 7q11.23 region in humans is prone to recurrent chromosomal rearrangement, due to the presence of low copy repeats that promote non-allelic homologous recombination. The most well characterized rearrangement of 7q11.23 is a hemizygous 1.5 million base pair (Mb) deletion spanning more than 25 genes. This deletion causes Williams-Beuren Syndrome (WBS; OMIM 194050), a multisystem developmental disorder with distinctive physical and behavioural features. Other rearrangements of the region lead to phenotypes distinct from that of WBS. Here we describe the first individual identified with duplication of the same 1.5 Mb region, resulting in severe impairment of expressive language, in striking contrast to people with WBS who have relatively well preserved language skills. We also describe the identification of a new gene for a severe form of childhood epilepsy through the analysis of individuals with deletions on chromosome 7 that extend beyond the boundaries typical for WBS. This gene, MAGI2, is part of the large protein scaffold at the post-synaptic membrane and provides a new avenue of research into both the molecular basis of infantile spasms and the development of effective therapies. Individuals with smaller than typical deletions of 7q11.23 have delineated a minimal critical region for WBS and have implicated two members of the TFII-I transcription factor family. To better understand the contribution of these genes to WBS, I have generated animal models with these genes deleted singly and in combination. Disruption of the first gene, Gtf2ird1, resulted in phenotypes reminiscent of WBS including alterations in social behaviour, natural fear response and anxiety. An alteration in serotonin function was identified in the frontal cortex and may be linked to these behavioural phenotypes. Together with a model for the second gene, Gtf2i, and the double deletion model that was generated using Cre-loxP technology, these resources will permit the study of the individual and additive effects of hemizygosity for Gtf2i and Gtf2ird1 and will greatly expand our understanding of the role the TFII-I gene family in WBS.

Deletion (Williams-Beuren syndrome (WBS)) and duplication (Dup7q11.23) of a common interval spanning 26 genes on chromosome 7q11.23 cause disorders with a spectrum of clinical, cognitive and behavioural symptoms. Studies of individuals with atypical deletions have implicated two genes, GTF2IRD1 and GTF2I. Here I describe the behavioural characterization of mice hemizygous for Gtf2i, or Gtf2ird1 and Gtf2i together, as well as mice with additional Gtf2i copies. Dosage changes in Gtf2i were associated with working memory impairment and separation anxiety, and possibly with general anxiety and repetitive behaviours. A potential cause of these phenotypes was found in brain tissue, where subcellular localization of the calcium channel TRPC3, which is regulated by GTF2I, was found to be altered. Collectively, these results provide a better understanding of the contributions of GTF2I to the cognitive and behavioural profile of WBS and Dup7q11.23 and identify a potential biological mechanism that may underlie some of the symptoms.

Deletion (Williams-Beuren syndrome (WBS)) and duplication (Dup7q11.23) of a common interval spanning 26 genes on chromosome 7q11.23 cause disorders with a spectrum of clinical, cognitive and behavioural symptoms. Studies of individuals with atypical deletions have implicated two genes, GTF2IRD1 and GTF2I. Here I describe the behavioural characterization of mice hemizygous for Gtf2i, or Gtf2ird1 and Gtf2i together, as well as mice with additional Gtf2i copies. Dosage changes in Gtf2i were associated with working memory impairment and separation anxiety, and possibly with general anxiety and repetitive behaviours. A potential cause of these phenotypes was found in brain tissue, where subcellular localization of the calcium channel TRPC3, which is regulated by GTF2I, was found to be altered. Collectively, these results provide a better understanding of the contributions of GTF2I to the cognitive and behavioural profile of WBS and Dup7q11.23 and identify a potential biological mechanism that may underlie some of the symptoms.