Molecular Mechanism of Hippocampal network excitability in a novel, in vivo model of Tuberous Sclerosis Complex

新型结节性硬化症体内模型中海马网络兴奋性的分子机制

• 批准号: 10447039
• 负责人: Kimberly Frances Raab-Graham
• 金额: $ 33.6万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447039
• 关键词: Address; Affect; Antiepileptic Agents; Back; Behavior; Behavioral; Biochemistry; Biological Assay; Bipolar Disorder; Brain; Brain Diseases; Brain region; Calcium; Calcium Channel; Calcium Signaling; Child; Code; Complex; Data; Dendrites; Development; Disease; Epilepsy; FRAP1 gene; Foundations; Future; Genes; Genetic; Genetic Translation; Glutamate Receptor; Health; Hereditary Disease; Hippocampus (Brain); Homeostasis; Human; Hyperactivity; Image; Impaired cognition; In Vitro; Individual; Infant; Intervention; Ion Channel; Isoxazoles; Knowledge; L-Type Calcium Channels; Lead; Learning; Life; Link; Major Depressive Disorder; Measures; Membrane; Memory impairment; Modeling; Molecular; Mus; Mutation; Nature; Neurobiology; Neurologic; Neurons; Organism; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phosphotransferases; Play; Pre-Clinical Model; Prevention; Propionates; Protein Biosynthesis; Proteins; Recycling; Regulation; Research Personnel; Rodent Model; Role; Schizophrenia; Seizures; Signal Pathway; Signal Transduction; Surface; Synapses; Synaptic plasticity; TSC1 gene; Testing; Time; Tuberous Sclerosis; Work; autism spectrum disorder; awake; burden of illness; clinical application; comorbidity; disability; early childhood; experimental study; gene therapy; in vivo; in vivo Model; individuals with autism spectrum disorder; interdisciplinary approach; link protein; mouse model; network dysfunction; network models; neuronal excitability; new therapeutic target; novel; novel therapeutic intervention; optogenetics; overexpression; prevent; receptor recycling; response; tool; voltage

PROJECT SUMMARY Overview: The project focuses on understanding the molecular basis of how disrupted calcium homeostasis leads to disrupted hippocampal network activity that results in maladaptive responses in neurons with TSC deficient signaling. Approximately 33% of children who have autism spectrum disorder (ASD) also have epilepsy. Early childhood seizures can result in compromised synaptic plasticity and cognitive impairment, suggesting that the hippocampus may be vulnerable to changes in network excitability. Despite the importance of this problem, the connection between seizure activity and development of ASD is poorly understood. Mammalian Target of rapamycin (mTOR) is a kinase that regulates protein synthesis and is overactive in many complex brain disorders. In the proposed studies, we focus on a mouse model of ASD, Tuberous Sclerosis Complex (TSC), which is a disorder that results from mutations in either the tsc1 or 2 genes. We propose that deficient TSC signaling leads to overactive mTOR and deficient protein synthesis that manifests as epilepsy and ASD. There is no cure for TSC, treatments are limited, and new therapeutic targets are needed. Our previous work has demonstrated that mTOR activity represses the expression of epilepsy-linked ion channels. The proposed studies extend our work to address the molecular mechanisms underlying hippocampal network hyperexcitability in TSC. We will take a multidisciplinary approach to critically test the prediction that reduced expression of the voltage-gated calcium channel subunit α2∂2 by overactive mTOR signaling in TSC leads to dysregulated calcium homeostasis and aberrant hippocampal network activity. (1) At the molecular level, we ask how α2∂2 expression is regulated by mTOR; (2) at the cellular level, we ask what is α2∂2’s role in dendritic calcium signaling and glutamate receptor recycling in TSC deficient dendrites; and (3) at the network level, we address the effect of α2∂2 in promoting aberrant hippocampal network activity. The proposed work is the first to bridge the gap between underlying molecular/cellular mechanisms and hippocampal network hyperexcitability in TSC, using a novel preclinical model to measure spike and seizure threshold for the first time. The strength of our approach allows us to also test several interventions using our novel optogenetic preclinical model of network activity. Notably, seizure medications do not target only the region of the brain that seizures originate, but can reduce hyperexcitable neurons in other parts of the brain, such as the hippocampus where ASD is tightly linked. Thus, we hypothesize that the hippocampus is vulnerable in children with TSC due to neuronal and network hyperexcitabillity. These studies form the foundation for promising new therapeutic strategies for TSC and other mTOR-related, complex brain disorders, with possible clinical applications.

项目总结

项目成果

Aberrant DJ-1 expression underlies L-type calcium channel hypoactivity in dendrites in tuberous sclerosis complex and Alzheimer's disease.

异常的 DJ-1 表达是结节性硬化症和阿尔茨海默病树突中 L 型钙通道活性低下的基础。

• DOI: 10.1073/pnas.2301534120
• 发表时间: 2023
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Niere,Farr;Uneri,Ayse;McArdle,ColinJ;Deng,Zhiyong;Egido-Betancourt,HaileyX;Cacheaux,LuisaP;Namjoshi,SanjeevV;Taylor,WilliamC;Wang,Xin;Barth,SamuelH;Reynoldson,Cameron;Penaranda,Juan;Stierer,MichaelP;Heaney,ChelcieF;Craf
• 通讯作者: Craf