L’autisme et la déficience intellectuelle (DI) définissent un spectre de troubles neuro-développementaux à composante génétique significative et impliquant au moins 1% de la population générale. Suite à l’identification de mutations dans les gènes PTCHD1 et GRID1 chez des sujets avec autisme et/ou DI, nous avons étudié leur rôle neuro-développemental par des approches translationnelles en modèle cellulaire et/ou animal Nos résultats montrent que PTCHD1 est un nouveau récepteur post-synaptique dont l'inactivation chez la souris Ptchd1-/y induit des troubles comportementaux et un dysfonctionnement des synapses glutamatergiques. En outre, PTCHD1 interagit avec les protéines PSD95, SAP102 (protéome postsynaptique glutamatergique), et RAC1 (cytosquelette d'actine et voie RhoGTPase). Concernant le gène GRID1, l’étude fonctionnelle in vitro d’une mutation homozygote (Arg161His) associée à une DI a révélé des altérations de la morphologie neuronale et synaptique, et souligne le rôle essentiel de ce récepteur sur la formation des terminaisons présynaptiques excitatrices. Ces données fournissent de nouveaux éléments sur les mécanismes physiopathologiques impliqués dans l’autisme et la DI, soulignant le rôle essentiel des récepteurs de la synapse excitatrice glutamatergique dans la cognition et la communication. / Autism and intellectual disability (ID) define a spectrum of neurodevelopmental disorders with a significant genetic component and involving at least 1% of the general population. Following the identification of mutations in the PTCHD1 and GRID1 genes in subjects with autism and/or ID, we sought to study their respective neurodevelopmental role by translational approaches in cell and/or animal models. Our results show that PTCHD1 is a novel post-synaptic receptor whose inactivation in Ptchd1-/y mice induces behavioral disorders and dysfunction of glutamatergic synapses. In addition, PTCHD1 interacts with PSD95, SAP102 (glutamatergic postsynaptic proteome), and RAC1 (actin cytoskeleton and RhoGTPase pathway) proteins. The in vitro functional study of a homozygous mutation (Arg161His) associated with ID revealed alterations in neuronal and synaptic morphology and underlines the essential role of this receptor in the formation of excitatory presynaptic terminations. These data provide new insights into the physiopathological mechanisms involved in autism and ID, highlighting the essential role of glutamatergic excitatory synapse receptors in cognition and communication.

<p>Developmental disabilities, including intellectual disability (ID), attention-deficit hyperactivity disorder (ADHD), and autism spectrum disorders (ASD), affect approximately 1 in 6 children in the United States. Attempts to produce treatment for developmental disabilities have been hampered by our current lack of understanding of the molecular mechanisms underlying these disorders. Advancements in genome sequencing and animal modeling technologies have proven to be an invaluable resource in the elucidation of potential disease mechanisms, with recent studies reporting novel mutations of the Ptchd1 and Shank3 genes in patients with developmental disabilities. Though these two genes have been proposed to play important roles in neural development, their function in the normal brain and defective behavioral output are poorly understood. </p><p>In this dissertation, I characterize the circuit and behavioral dysfunction of the genetically-engineered Ptchd1 and Shank3 knockout mice. With respect to Ptchd1, I found that expression is developmentally enriched in the thalamic reticular nucleus (TRN), which is a group of GABAergic neurons serving as the major source of inhibition for thalamo-cortical neurons. Slice and in vivo electrophysiological experiments revealed that deletion of this gene in mice disrupts SK2 currents and burst firing mechanisms in the TRN, a region that has previously been shown to play an important role in sleep, attention, and cognition. Consistent with clinical findings, Ptchd1 knockout mice display behavioral phenotypes indicative of hyperactivity, attention deficits, motor dysfunction, hyperaggression, and cognitive impairment. Interestingly, attention-like deficits and hyperactivity are rescued by SK2 pharmacological enhancement, suggesting a potential molecular target for developing treatment. </p><p>Shank3 knockout mice display ASD-like phenotypes, including social interaction deficits and repetitive behaviors. In addition, biochemical, electrophysiological, and morphological abnormalities were discovered in the medium spiny neurons (MSNs) of these mice. However, the exact neural circuits and cell types responsible for the autistic-like behaviors have not been identified. To address this important question, I developed a new conditional Shank3 knockout mouse. Importantly, the behavioral abnormalities reported in the original Shank3 knockout mice were recapitulated in this novel conditional Shank3 knockout mouse, indicating that this mouse may be useful for future pathway-specific dissections of ASD-like behaviors. Together, these two sets of studies not only provide mouse models for dissecting the function of PTCHD1and SHANK3 in normal and abnormal neural development, but also demonstrate a critical role for PTCHD1 in TRN neurons and SHANK3 in MSN cells and in the case of PTCHD1, identify potential cellular and circuit pathway targets for much-needed pharmacological intervention.</p> / Dissertation