Roles of glycinergic neurons in Dravet syndrome-associated disordered breathing and mortality

甘氨酸能神经元在 Dravet 综合征相关呼吸障碍和死亡率中的作用

• 批准号: 10532702
• 负责人: Brenda Milla
• 金额: $ 4.47万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532702
• 关键词: Affect; Animals; Apnea; Behavioral; Bradycardia; Brain Stem; Breathing; Carbon Dioxide; Cardiac; Cause of Death; Cells; Cessation of life; Chemoreceptors; Development; Diagnostic tests; Electrophysiology (science); Epilepsy; Exhibits; Fever; Foundations; GLYT2; Genes; Genotype; Goals; Heterozygote; Hypoventilation; Incidence; Modeling; Mus; Mutation; Neurons; Pathology; Patients; Phenotype; Prosencephalon; Reporting; Research; Respiration Disorders; Respiratory Center; Respiratory Failure; Respiratory physiology; Role; SCN1A protein; Seizures; Slice; Testing; Tissues; Transcript; Whole Body Plethysmography; Work; dravet syndrome; electrical property; experimental study; in vivo; inhibitory neuron; insight; mortality; neural; novel; premature; respiratory; response; sudden unexpected death in epilepsy; voltage

Summary Dravet syndrome (DS) is a severe form of epilepsy with a high rate of SUPEP. Respiratory failure is a leading cause of SUDEP, and DS patients' frequently exhibit disordered breathing. However, mechanisms underlying respiratory dysfunction in DS are unknown. Evidence suggests cortical seizures activate inhibitory projections to suppress brainstem function and result in death; however, a yet unexplored possibility is that DS-associated mutations directly affect brainstem respiratory centers and serve as a common substrate for both seizure and respiratory dysfunction. We recently showed that Scn1a transcript is highly expressed in brainstem inhibitory neurons, and expression of a DS-associated Scn1a mutation (A1783V) in inhibitory neurons resulted in cell autonomous loss of neural activity and disruption of respiratory function at the cellular and whole-animal levels. Therefore, I hypothesize that loss of Scn1a function directly impacts brainstem respiratory control. To test this, I will disrupt Scn1a function globally (Scn1a-/+), specifically in all VGAT+ inhibitory neurons and only in glycinergic neurons (GlyT2:A1783V) and determine whether these animals exhibit disordered breathing, seizures or premature death (Aim 1), and altered cellular activity of respiratory neurons (Aim 2). This work will provide novel insight into roles of glycinergic neurons in DS, and determine the extent to which loss of Scn1a function directly affect brainstem function.

总结 Dravet综合征（DS）是一种严重的癫痫，SUPEP发生率很高。呼吸 衰竭是SUDEP的主要原因，并且DS患者经常表现出呼吸紊乱。 然而，DS呼吸功能障碍的潜在机制尚不清楚。证据 表明皮层癫痫发作激活抑制性投射以抑制脑干功能， 导致死亡;然而，一个尚未探索的可能性是，DS相关突变直接 影响脑干呼吸中枢，并作为癫痫发作和 呼吸功能障碍我们最近发现Scn 1a转录本在大肠杆菌中高度表达， 脑干抑制性神经元，以及DS相关Scn 1a突变（A1783 V）在 抑制性神经元导致细胞自主性神经活动丧失， 呼吸功能在细胞和整个动物水平。因此，我推测， scn 1a功能直接影响脑干呼吸控制。为了验证这一点，我将破坏Scn 1a 全局功能（Scn 1a-/+），特别是在所有VGAT+抑制性神经元中，仅在甘氨酸能神经元中 神经元（GlyT 2：A1783 V），并确定这些动物是否表现出呼吸紊乱， 癫痫发作或过早死亡（目的1），呼吸神经元的细胞活性改变（目的2）。 这项工作将为DS中甘氨酸能神经元的作用提供新的见解，并确定其作用。 Scn 1a功能丧失直接影响脑干功能的程度。