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Role of mTORC1 dependent translation in neurological deficits of TSC

mTORC1 依赖性翻译在 TSC 神经功能缺陷中的作用

基本信息

批准号：
10424796
负责人：
Matthew Binder
金额：
$ 6.76万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10424796
关键词：
Address Anatomy Attenuated Axon Behavior Behavioral Binding Proteins Bioinformatics Brain CRISPR/Cas technology Caregivers Clinical Complex Corpus striatum structure Development Disease Electrophysiology (science)Electroporation Epilepsy Etiology Eukaryotic Initiation Factors FRAP1 gene Genes High Prevalence Hyperactivity Hypertrophy Incidence Individual Knowledge Laboratories Lead Medial Microscopy Modeling Molecular Mus Mutation Neurologic Neurologic Deficit Neurons Pathologic Patients Phenotype Population Prefrontal Cortex Property Ras homolog enriched in brain Research Role SDZ RAD Seizures Signal Pathway Signal Transduction Social Behavior Social Interaction Synapses TSC1 gene TSC2 gene Testing Therapeutic Transgenic Model Translations Tuberous Sclerosis Ultrasonics Western Blotting autism spectrum disorder autistic axon growth behavioral phenotyping comorbidity design developmental disease effective therapy hippocampal pyramidal neuron in utero inhibitor insight mouse model novel prevent relating to nervous system small hairpin RNA social synaptic function trait transcriptome sequencing translatome vocalization

项目摘要

ABSTRACT Tuberous sclerosis complex (TSC) is a developmental disorder caused by a mutation in the TSC1 or TSC2 gene. Mutations in TSC genes result in hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1), a signaling pathway vital for development. Individuals with TSC present with a high incidence of neurological conditions, among the most prevalent of which are epilepsy and autism spectrum disorder (ASD). While mTORC1 inhibitors can effectively attenuate seizures, they do not improve TSC’s autistic comorbidity. Thus, there is a critical need to better understand the etiology of autism traits to identify novel treatments. Our laboratoryhasdevelopedamousemodelofTSCin which constitutively active Rheb is expressed in developing cortical neurons of the medial prefrontal cortex (mPFC), a region that is dysregulated in TSC and implicated in ASD. This model allows for a more precise activation of mTORC1 than transgenic models and is thus ideally suited to parse out complex etiology. Using this model, our lab found alterations in local mPFC connectivity that resemble the pathological changes in TSC’s autistic comorbidity. Moreover, when aberrant cap dependent translation was normalized via the activation of a translational repressor, the observed alterations were prevented. While connectivity has been examined within the mPFC in a hyperactive mTORC1 state, the accompanying behavioral phenotype has not been assessed nor have mTORC1’s effects on specific subcortical projections from the mPFC. To this end, the striatum is a compelling target, as it is heavily interconnected with the mPFC and is integral to socio-communicative behaviors (core deficits in ASD). However, axonal connectivity in TSC is understudied and mPFC-striatal projections have not been assessed. Furthermore, while normalizing translation can mitigate cellular alterations in hyperactive mTORC1 conditions, the specific downstream molecular alterations that account for these changes are unknown, as are their efficacy to attenuate behavioral deficits. Therefore, the specific aims are to: 1). Determine whether hyperactive mTORC1 in mPFC-striatal projections contributes to socio-communicative deficits. 2). Determine whether increasing mTORC1 activity during early mPFC development leads to alterations in cortico-striatal projections resulting in an excitation-inhibition imbalance in the striatum. 3). Determine whether altered cap-dependent translation and downstream molecules contribute to alterations in axonal connectivity and socio-communicative deficits. To address these aims, in utero electroporation (IUE) will be used to increase mTORC1 in pyramidal neurons of the mPFC. Vocalization and social interaction tests will assess the phenotype, whereas lightsheet microscopy, axonal tracing, and electrophysiology will assess mPFC-striatal connectivity. Potential candidate molecules downstream of translation that control axonal growth will be identified via Trap, and shRNA will be designed to assess the effects of normalizing the identified genes on socio-communicative deficits and alterations in mPFC-striatal connectivity.

摘要