Cellular and circuit function of Ndnf-expressing interneurons in a mouse model of a neurodevelopmental disorder
Cellular and circuit function of Ndnf-expressing interneurons in a mouse model of a neurodevelopmental disorder
批准号:
10678812
负责人:
Sophie Rose Liebergall
金额:
$4.77万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-06-01 至 2026-05-31
关键词:
Action PotentialsAcuteAgeAnimal ModelAxonBiological ModelsBrainCalciumCaregiversCellsCellular MorphologyCerebral cortexChildChronicDNA Sequence AlterationDataDefectDendritesDevelopmentDevelopmental Delay DisordersDiagnosisDiseaseEconomicsElectrical SynapseElectrophysiology (science)EmotionalEpilepsyExperimental ModelsFunctional disorderFutureGenerationsGenesGoalsHealthHeterozygoteHumanImageImaging TechniquesImpairmentIn VitroInduced pluripotent stem cell derived neuronsIntellectual functioning disabilityInterneuronsLocomotionLoss of HeterozygosityMediatingMediatorMolecularMorphologyMusNeocortexNeuroanatomyNeurodevelopmental DisorderNeuronsOpticsParvalbuminsPathogenesisPathogenicityPathologyPatientsPersonal SatisfactionPhysiciansPlayPopulationPositioning AttributePresynaptic TerminalsPropertyPublishingPyramidal CellsQuality of lifeRegulationResistanceRestRoleSCN1A proteinSchizophreniaScientistSensorySliceSodiumSodium ChannelSomatostatinSubcellular AnatomySynapsesSynaptic TransmissionTechniquesTherapeutic InterventionTrainingTranscriptUnited StatesVariantVasoactive Intestinal PeptideWild Type MouseWorkautism spectrum disorderbiocytincareercell behaviorclinically relevantdensitydisease mechanisms studydravet syndromeeffective therapyexcitatory neuronexperimental studygamma-Aminobutyric Acidin vivoin vivo calcium imagingin vivo imagingmouse modelmultiphoton imagingneocorticalnervous system disorderneurotrophic factornew therapeutic targetnovelnovel therapeuticsoptogeneticspatch clampreconstructionsocialsomatosensorytargeted treatmenttherapeutic targettranscriptomicstransmission processtwo-photonvoltage
中文摘要
项目总结/文摘
英文摘要
PROJECT SUMMARY/ABSTRACT
Each year, 1 in 6 children are diagnosed with a neurodevelopmental disorder such as autism spectrum disorder,
intellectual disability, or epilepsy. Such disorders severely impact the emotional, social, physical, and economic
wellbeing of patients and their caregivers, and a poor understanding of the underlying pathophysiology of these
disorders has slowed the discovery of effective therapies. There is evidence, however, that neurodevelopmental
disorders as a class are associated with selective dysfunction of GABAergic inhibitory interneurons in the
cerebral cortex.
Dravet Syndrome, caused by pathogenic variants in the SCN1A gene encoding the Nav1.1 voltage-gated sodium
channel a subunit, is a canonical example of a neurodevelopmental disorder caused by interneuron dysfunction,
as interneurons in the neocortex preferentially rely on Nav1.1 for action potential generation and propagation.
Importantly, cerebral cortical interneurons are a functionally heterogenous population; therefore, understanding
the contribution of different classes of interneurons to microcircuit function in normal brain, and dysfunction in
the setting of pathology, is essential for further elucidating the mechanisms of neurodevelopmental disorders.
In this proposal, I will determine the function or dysfunction of the least studied major population of neocortical
interneurons, those expressing Neuron-Derived Neurotrophic Factor (Ndnf), within cerebral cortical microcircuits
in Dravet Syndrome. These cells are enriched in layer 1 of neocortex, where they are thought to play a role in
sensory processing and regulating inhibitory tone in the cortex. Using a clinically-relevant and well-characterized
mouse model of Dravet Syndrome, I will first establish the electrophysiologic, synaptic, and morphologic
properties of Ndnf-expressing interneurons in Scn1a+/- mice relative to wild-type mice in vitro (Aim 1). I will then
determine the behavior of these cells within cortical microcircuits in Scn1a+/- mice relative to wild-type in vivo
using multiphoton imaging and optogenetic approaches (Aim 2). This proposal will not only provide novel data
on an understudied interneuron subtype, both in health and disease, but also provide training in a suite of
advanced electrophysiologic and optical techniques that will serve to train the applicant towards a future career
as a physician-scientist studying circuit dysfunction in neurological disorders and development of new therapies
and cures.
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