The Role Of The Nmda Receptor In Shaping Cortical Activity During Development

Currently, it is estimated that neuropsychiatric disorders will affect 20-25% of humans in their lifetime. These disorders are a major cause of mortality, suffering, and economic cost to society. Within this broad class, neurodevelopmental disorders (NDDs), including intellectual disability, autism spectrum disorder, and schizophrenia, are estimated to affect 2-5% percent of the world population. Devastatingly, we lack fundamental treatments for NDDs, which have proved some of the most imposing disorders to understand scientifically. The challenge is twofold: first, NDDs affect the most complex aspects of human cognition; second, pathogenesis begins early in neural circuit development, but we lack predictive biomarkers before overt behavioral deficits are apparent. Although we have identified many genes associated with these disorders, how underlying genetic disruptions lead to pathological neural network development and function remains unclear. The overarching framework of this dissertation is that all NPDs are disorders of distributed neural networks, and pathophysiology must be understood at this level to effectively intervene clinically. The cerebral cortex is necessary for complex human capacities, and cortical dysfunction is hypothesized to be central to the pathophysiology of NDDs. NMDA glutamate receptors (NMDARs) are important for the development of local circuit features in the cortex, for normal neurocognitive function, and are strongly implicated in NDDs. However, the role of NMDARs in the development of the large-scale cortical network dynamics that underly higher cognition has not been well examined. Understanding the role of NMDARs at this network level is critical because large-scale “functional connectivity” patterns are thought to be hallmarks of normal cortical function, are hypothesized to be disrupted in NDDs, and may be detectable in humans using non-invasive neuroimaging or electrophysiology. In the studies presented in this dissertation, I (in collaboration and with the support of my colleagues) tested the role of the NMDAR in shaping large-scale cortical network organization using in vivo widefield imaging of whole cortex spontaneous activity in developing mice. I found that NMDAR function in the lineage that includes cortical excitatory neurons and glia, specifically, was critical for the elaboration of normal cortical activity patterns and dynamic network organization. In the first set of experiments, NMDARs were deleted in glutamatergic excitatory neurons (Emx1-cre+/WT/Grin1f/f ; referred to as EX-NMDAR KO mice) or GABAergic inhibitory neurons (Nkx2.1+/WT/Grin1f/f; referred to as IN-NMDAR KO mice). The developing cortex normally exhibits a diverse range of spatio-temporal patterns, reflecting the emergence of functionally associated sub-networks. In EX-NMDAR KO mice, normal patterns of spontaneous activity were severely disrupted and reduced to a nearly one-dimensional dynamic space dominated by large, cortex-wide events. Interestingly, in IN-NMDAR KO mice, the structure and complexity of spontaneous activity was largely normal. In the next set of experiments, I tested the role of extrinsic thalamic neurotransmission on cortical activity during development. Deleting the vesicular glutamate transporter from thalamic neurons while leaving cortical NMDARs intact (Sert-Cre+/−,vglut1−/−,vglut2fl/fl; referred to as TH-VG KO mice) led to a shift in cortical activity patterns towards large domains of activity, reminiscent of patterns observed in EX-NMDAR KO mice. This manipulation also reduced the dimensionality of cortical activity, though not as severally as in EX-NMDAR KO mice. In a final set of experiments, I tested cortical activity in three established mouse models of mono-genetic causes of NDDs in humans: the FMR1-KO mouse based on Fragile X Syndrome, the CNTNAP2-KO mouse, and the TS2-neo mouse based on Timothy Syndrome. In all three of these mouse models, I found that large-scale cortical activity patterns were largely normal, but there was a statistically significant shift towards reduced cortex-wide synchrony and increased dimensionality of spontaneous activity, which may be consistent with the disconnectivity hypothesis of autism. In a final set of experiments, we tested our hypothesis, based on past literature and our results in EX-NMDAR KO and TH-VG KO mice, that the disruptions in cortical activity was predominantly due to the developmental loss of activity-dependent wiring of circuits. To test the developmental versus acute role of NMDAR function in shaping cortical activity, I blocked NMDAR pharmacologically in wild-type mice. I found that acute NMDAR blockade shifted cortical activity to a restricted dynamic space similar to that observed in EX-NMDAR KO mice and more extreme than that observed in TH-VG KO mice. These results strongly reinforce the critical role of NMDAR in shaping cortical activity during development, and suggest that a substantial component of that may be through NMDAR’s role in synaptic transmission and moment to moment cortex-wide circuit function. Overall, these results provide critical insight into the role of NMDARs and the glutamatergic system in cortical network functional organization during development. Specifically, they highlight the essential role of NMDARs in excitatory neurons on the functional connectivity and dynamic repertoire of the cortical network during development. These results make novel contribution to our understanding of how NMDARs may contribute to the pathophysiology of NDDs. Specifically, they contribute powerful new insight into to a critical mechanistic question about the cell-specific role of NMDARs in the pathophysiology of schizophrenia and the mechanisms of NMDAR antagonists, which have transformed psychiatry recently due to their rapid-acting anti-depressant and anti-suicidal properties. Furthermore, they identify a patterns of large-scale network dysfunction that might be detectable in humans using noninvasive functional imaging or electrophysiology

Compréhension intégrée de quatre syndromes génétiques impliqués dans la déficience intellectuelle via des biomarqueurs électrophysiologiques, les manifestations comportementales, le fonctionnement adaptatif et les interventions disponibles sur le plan clinique.

La trisomie 21 (T21), le Syndrome X Fragile (SXF), la Sclérose tubéreuse de Bourneville (STB) et les mutations SYNGAP1 sont causés par des dysfonctionnements des voies moléculaires qui entraînent notamment un déséquilibre dans l’excitation et l’inhibition de l’activité neuronale qui aurait des impacts sur le développement et le fonctionnement du cerveau. Toutefois, il est difficile de faire le pont entre les déséquilibres moléculaires observés dans les modèles animaux et les particularités structurelles, fonctionnelles et cognitives observées dans ces syndromes chez l’humain. À notre connaissance, peu d’études ont comparé différents syndromes génétiques sur les processus sensoriels, l’apprentissage de base ou encore leurs caractéristiques comportementales en utilisant des paradigmes similaires et translationnels, permettant de mieux comprendre leurs particularités. Le premier volet de cette thèse vise à identifier si l’activité électroencéphalographique serait un biomarqueur adéquat représentant les altérations neurobiologiques tant des processus sensoriels que d’apprentissage chez les humains présentant ces syndromes. L’étude #1 avait comme objectif de décrire le traitement sensoriel auditif, comme il s’agit d’un processus élémentaire, et ce, chez les mutations SYNGAP1 qui représentent une condition génétique encore peu étudiée chez l’humain. Les résultats ont d’ailleurs permis d’identifier une diminution de la synchronisation de phase et une augmentation de la puissance dans la bande gamma qui distinguent cette condition génétique tant des participants sans DI que de la T21. Toujours dans l’esprit d’identifier des biomarqueurs électroencéphalographiques, mais cette fois au niveau d’un processus cognitif de base, l’étude #2 avait pour objectif de comparer tous ces syndromes dans un paradigme de suppression neuronale (SN) afin de vérifier la présence de SN et de comparer l’apprentissage de base chez ces populations. Les résultats ont identifiés que la T21 et le SXF présentaient tous les deux un patron de SN et que le SXF présentait relativement une plus forte habituation indiquant des particularités spécifiques selon les syndromes. Le deuxième volet, davantage clinique, permet de comparer les profils comportementaux associés au fonctionnement adaptatif entre les syndromes et à décrire les pistes d’intervention existantes. L’étude #3 a notamment mis en évidence que le QI et les symptômes de TDAH sont associés au fonctionnement adaptatif auprès de ces différents syndromes dont le SXF et la STB. Cet article a aussi permis de décrire les profils comportementaux de ces mêmes conditions en révélant davantage de difficultés rapportées chez les individus présentant un SXF, alors que la T21 présentait moins de particularités cliniques au niveau comportemental. Enfin, l’article #4 a mis en lumière diverses interventions utilisées auprès de la population présentant une DI notamment des stratégies cognitivo-comportementales et compensatoires. Cette thèse permet donc de dresser un portrait spécifique de ces syndromes génétiques concernant leur signature électrophysiologique lors du traitement sensoriel et de l’apprentissage ainsi que sur le plan des comorbidités comportementales et de leur relation avec le fonctionnement adaptatif, pour ensuite aborder les interventions actuelles en DI. Les diverses particularités identifiées à plusieurs niveaux ont permis de générer des suggestions pouvant guider certaines interventions futures.Down syndrome (DS), Fragile X syndrome (FXS), Tuberous sclerosis complex (TSC) and SYNGAP1 mutations are caused by dysfunctions of the molecular pathways which lead among others to an imbalance in excitation and inhibition of the neuronal activity that would impact the brain development and its functioning. However, it is difficult to directly bridge the gap between the molecular imbalances observed in animal models with the structural, functional and cognitive characteristics observed in human with these syndromes. To our knowledge, few studies have compared those different genetic syndromes on sensory processing, basic learning or on their behavioural issues using similar and translational paradigms then allowing a better understanding of their specificities. The first part of this thesis aims to identify whether electroencephalographic activity would be an adequate biomarker representing neurobiological alterations both in sensory processing and learning in humans with these syndromes. The goal of study #1 was to describe auditory sensory processing, as a very first basic process, in SYNGAP1 mutations being a genetic condition still little studied in humans. Results showed a decrease in phase synchronization and an increase in the power of gamma band which distinguish this genetic condition both from participants without ID and from DS. Still in order to identify electroencephalographic biomarkers, but this time at a basic cognitive level, study #2 aimed to compare all these syndromes in a repetition suppression (RS) paradigm in order to observe the presence of RS and compare basic learning in these populations. The results identified a RS pattern in both DS and FXS. FXS also exhibited relatively higher habituation then indicating specific features according to the syndrome. The second part, addressing clinical aspects, permits to compare the behavioural profiles associated with adaptive functioning between syndromes and to describe existing interventions on ID population. Study #3 notably highlighted that IQ and ADHD symptoms are associated with adaptive functioning especially in FXS and TSC. This article also made it possible to describe the behavioural profiles of these syndromes, revealing more difficulties reported in individuals with FXS, while DS presented fewer behavioural issues. Finally, article #4 highlighted various interventions used with ID population, notably cognitive-behavioural and compensatory strategies. This thesis therefore makes it possible to gain a better understanding of these genetic syndromes concerning their electrophysiological signature during sensory processing and learning as well as in terms of behavioural comorbidities and their relationship with adaptive functioning, to then address current ID interventions. These different syndromic particularities identified at several levels made it possible to generate suggestions that could guide future interventions in this field

Modern Developments in Transcranial Magnetic Stimulation (TMS) – Applications and Perspectives in Clinical Neuroscience

Transcranial magnetic stimulation (TMS) is being increasingly used in neuroscience and clinics. Modern advances include but are not limited to the combination of TMS with precise neuronavigation as well as the integration of TMS into a multimodal environment, e.g., by guiding the TMS application using complementary techniques such as functional magnetic resonance imaging (fMRI), electroencephalography (EEG), diffusion tensor imaging (DTI), or magnetoencephalography (MEG). Furthermore, the impact of stimulation can be identified and characterized by such multimodal approaches, helping to shed light on the basic neurophysiology and TMS effects in the human brain. Against this background, the aim of this Special Issue was to explore advancements in the field of TMS considering both investigations in healthy subjects as well as patients

Visuo-perceptual correlates of autistic trait expression in children with Fragile X syndrome and Down Syndrome

Autism Spectrum Disorder (ASD) is a clinical umbrella term used to reference a neurodevelopmental profile of socio-communicative impairment and restricted, repetitive patterns of behaviour (RRB). In most cases, ASD is ‘idiopathic’ meaning that genetic aetiology is poorly defined. In other cases, ASD may present in genetic syndrome groups of known aetiology, like Fragile X syndrome (FXS) and Down syndrome (DS). There is research to suggest that these ‘syndromic’ forms of ASD manifest distinctly in terms of behavioural symptomatology; however, beyond this level of description, we know little of the nature of these comorbidities. Visuo-perceptual irregularities are well documented in idiopathic ASD populations; in particular, spatial orienting and visual search abilities are known to be affected. Prior to this doctorate research, it remained to be seen whether behavioural manifestations of autistic-like impairment in FXS and DS were characterised by similar visuo-perceptual abnormalities. This thesis presents a series of eye-tracking studies designed to characterise syndromic forms of ASD according to associated visuo-perceptual mechanism. The work that is presented here examines the visuo-perceptual correlates of autistic trait expression in neuro-typical (NT) children (n=56) and in three clinical paediatric cohorts: idiopathic ASD (n=16), FXS (n=7) and DS (n=15), focusing specifically on attentional disengagement and visual search performance. The results are consistent with the notion of syndrome-specific profiles of autistic-like impairment, extending the literature and elucidating the complex heterogeneity that is associated with ASD. Moreover, they illustrate the value of progressing beyond superficial behavioural indices of autistic-like impairment to examine, in a more fine-grained way, the neurocognitive features underpinning comorbid expressions of autistic-like deficit

Sleep patterns and creativity in children and adolescents with and without high functioning autism (HFA): a descriptive study and an intervention trial

Sleeplessness is common in childhood especially in some clinical groups and it has negative effects on child and family functioning. There is limited data suggesting a link between lack of sleep and impaired creativity and more studies are needed especially with children with autism for whom creativity is compromised and risk of sleeplessness is high. The adverse affects on children's neurobehavioral functioning caused by insufficient sleep might be reversed by removal of the sleep disturbance as a means of improving overall function of the child. The treatment of choice for childhood sleeplessness problems are behavioural approaches however they have not been sufficiently evaluated with school age typically developing children (TC) or with children with high functioning autism (HFA) and further, parents often have limited access to such treatments. Therefore this study aimed to explore the relationship between sleep and neurobehavioral functioning and creativity of children (with and without HFA) and maternal mental health by means of a descriptive study (n=65) and to evaluate the efficacy of booklet behavioural intervention for sleeplessness problems, via a multiple baseline design (n=9), and its indirect effects on children's creativity. Sleep was assessed by parent and child sleep reports as well as by actigraphy. Children's creativity was measured using the Torrance Test of Creative Thinking and newly developed tests of creativity. Measures of child neurobehavioral functioning and parental mental health were also employed. The results suggested that sleeplessness was associated with impaired child neurobehavioral functioning and maternal mental health and with reduced creativity in TC only. The booklet-based behavioural intervention appeared to be effective for the treatment of sleeplessness in TC although no associated changes in creativity were consistently found. The booklet was less useful for children with HFA. The thesis argues that sleeplessness impairs high level cognitive ability in children and affects maternal mental health. The results are clinically useful as they support the use of booklet-based behavioural interventions for sleeplessness in school age TC. The efficacy of such approach with children with HFA needs to be further explored. Nocturnal mental over-activity appeared responsible for the maintenance of sleeplessness in TC and HFA. This has important clinical implications when considering appropriate intervention approaches for this age group

Sleep problems in young people with 22q11.2 Deletion Syndrome: associations with the neurodevelopmental phenotype

This is the first thesis to explore sleep problems in young people with 22q11.2 Deletion Syndrome. This thesis includes both subjective and objective methods of sleep assessment which have contributed to furthering academic knowledge of sleep problems in 22q11.2DS. Firstly, the prevalence, nature and severity of sleep problems in a sample of young people with 22q11.2DS compared to their unaffected siblings was determined. The prevalence of sleep problems was high in young people with 22q11.2DS (~60%) and that the high preponderance remained stable in small subsamples of toddlers, adolescents and adults. The nature of sleep problems in the young people with 22q11.2DS was elucidated, showing that more sleep problems associated with poorer psychopathology and cognitive impairment. Building on the foundations of the subjective assessment of sleep, objective measures were introduced to begin to explore the physiology of sleep in these young people. A pilot study with a small typically developing sample of young people was conducted to assess the feasibility of an overnight sleep study. Resultantly, an overnight sleep study was developed in a subsample of young people with 22q11.2DS and their unaffected siblings which included polysomnography (PSG), two-week actigraphy assessments with a sleep diary and validated sleep questionnaires. Actigraphy-derived sleep parameters were compared between 22q11.2DS and siblings showing some differences, in addition to differences in sleep parameters between the objective and subjective methods of assessment. Investigations into sleep architecture were few and small but provided a basis to build from when exploring the neurophysiology of sleep in young people with 22q11.2DS. Overall, the results from this thesis could have important implications for understanding sleep and its relationship with the neurodevelopmental phenotype in 22q11.2DS