The brain network is a multiscale hierarchical organization from neurons and local circuits to macroscopic brain areas. The precise synaptic transmission at each synapse is therefore crucial for neural communication and the generation of orchestrated behaviors. Activation of presynaptic voltage-gated calcium channels (CaV2) initiates synaptic vesicle release and plays a key role in neurotransmission. In this dissertation, I have aimed to uncover how CaV2 activity affects synaptic transmission, circuit function and behavioral outcomes using Caenorhabditis elegans as a model. The C. elegans genome encodes an ensemble of highly conserved neurotransmission machinery, providing an opportunity to study the molecular mechanisms of synaptic function in a powerful genetic system. I identified a novel gain of function CaV2α1 mutation that causes CaV2 channels to activate at a lower membrane potential and slow the inactivation. Cell-specific expression of these gain-of-function CaV2 channels is sufficient to hyper-activate neurons of interest, offering a way to study their roles in a given circuit. CaV2(gf) mutants display behavioral hyperactivity and an excitation-dominant synaptic transmission. Imbalanced excitation and inhibition of the nervous system have been associated with several neurological disorders, including Familial Hemiplegic Migraine type 1 (FHM1) which is caused by gain- of-function mutations in the human CaV2.1α1 gene. I showed that animals carrying C. elegans CaV2α1 transgenes with corresponding human FHM1 mutations recapitulate the hyperactive behavioral phenotype exhibited by CaV2(gf) mutants, strongly suggesting the molecular function of CaV2 channels is highly conserved from C. elegans to human. Through performing a genome-wide forward genetic screen looking for CaV2α(gf) suppressors, we isolated new alleles of genes that required for CaV2 trafficking, localization and function. These regulators include subunits of CaV2 channel complex, components of synaptic and dense core vesicle release machinery as well as predicted extracellular proteins. Taken together, this work advances the understanding of CaV2 malfunction at both cellular and circuit levels, and provides a genetically amenable model for neurological disorders associated with excitation-inhibition imbalance. Additionally, through identifying regulators of CaV2, this research provides new avenues for understanding the CaV2 channel mediated neurotransmission and potential pharmacological targets for the treatments of calcium channelopathies.

Les études épidémiologiques ont démontré un risque accru d’autisme chez les enfants nés d’une mère hospitalisée pour infection au cours de la grossesse. L’imitation d’une infection virale dans le but de déclencher une Activation Immunitaire Maternelle (MIA) a été réalisé avec succès dans des modèles animaux. Ceci a démontré qu’une MIA conduit à des altérations physiologiques et comportementales sur le long terme. Notre but consistait à étudier la présence de séquelles néonatales chez des souris nées de mère MIA. Nous avons observé que la MIA altère l’activité et la morphologie des neurones dès la naissance, et que ces modifications restaient présentes dans les animaux âgés de deux semaines. La MIA subie au cours de la grossesse altère donc les neurones dès la naissance. / Epidemiological studies have shown an increased risk for autism in children born from mothers hospitalized for infection during pregnancy. Mimicking a maternal infection during pregnancy to trigger a Maternal Immune Activation (MIA) has been successfully achieved in animal models, showing that it leads to long term physiological and behavioural alterations. Our goal was to investigate neonatal sequels in MIA mice offspring. We found that already at birth MIA alters neuronal activity and morphology, and these changes were still present in two-week-old animals. Consequently, MIA during pregnancy alters neurons already at birth.