Cell Type Specific Genetic Manipulation to Dissect Cholinergic Interneuron Function and Plasticity in a Symptomatic Model of DYT1 Dystonia

细胞类型特异性基因操作剖析 DYT1 肌张力障碍症状模型中的胆碱能中间神经元功能和可塑性

• 批准号: 10548214
• 负责人: WILLIAM T. DAUER
• 金额: $ 50.49万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548214
• 关键词: Ablation; Address; Adolescent; Autopsy; Autoreceptors; Behavioral; Biological Models; Brain; Brain Diseases; Cells; Chemicals; Corpus striatum structure; Data; Defect; Disease; Disease model; Drug usage; Dyskinetic syndrome; Dystonia; Electrophysiology (science); Elements; Functional disorder; Generations; Genetic; Genetic study; Glutamic Acid; Goals; Human; Interneuron function; Interneurons; L-DOPA induced dyskinesia; Literature; Machine Learning; Modeling; Morphology; Motor; Movement; Mus; Muscarinics; Nerve Degeneration; Neuronal Dysfunction; Neurons; Output; Parkinson Disease; Pathogenesis; Patients; Pharmaceutical Preparations; Publishing; Role; Signal Transduction; Slice; Symptoms; Synapses; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; TorsinA; cell type; cholinergic; cholinergic neuron; conditional knockout; design; designer receptors exclusively activated by designer drugs; effective therapy; genetic approach; genetic manipulation; loss of function mutation; motor behavior; motor disorder; multidisciplinary; nervous system disorder; neurodevelopment; neuron loss; neuropathology; novel; novel strategies; optogenetics; predictive modeling; prevent; targeted treatment; tomography; tool; translational study

Project Summary/Abstract Cholinergic neurons (ChIs) are a central but poorly understood element of striatal circuitry. A considerable literature strongly implicates ChI dysfunction in the pathogenesis of abnormal movements, especially in dystonia and levodopa-induced dyskinesias in Parkinson disease. A common theme of these studies is that maladaptive plastic changes cause aberrant ChI output and connectivity, promoting motor dysfunction. The central goal of this proposal is to advance understanding of the cellular and synaptic mechanisms through which ChIs cause motor dysfunction by employing novel selective genetic and chemical strategies in a recently validated model of DYT1 dystonia. Conditional Knock Out of torsinA from all striatal neurons (using Dlx5/6-Cre; “Dlx-CKO”) causes selective neurodegeneration of dorsolateral striatal ChI. ChI degeneration occurs roughly coincident with the juvenile onset of abnormal twisting movements in these mice, and selective ChI abnormalities are also present in postmortem tissue from DYT1 subjects. These movements are suppressed by the same anti-muscarinic compounds used to treat patients with DYT1 dystonia, establishing model therapeutic validity and suggesting shared pathophysiology with human dystonia. Surviving striatal ChIs are enlarged and hyperexcitable, and receive aberrant synaptic inputs. Selective ablation of these surviving ChI suppresses abnormal twisting, implicating these cells as key contributors to abnormal movements. Based on these data, we hypothesize that maladaptations in surviving ChIs drive motor dysfunction. Successful completion of the proposed studies will fundamentally advance understanding of maladaptive mechanisms whereby ChI function and connectivity drive abnormal movements, information highly significant for multiple striatal diseases. We will first address our hypothesis by testing the necessity of striatal ChI dysfunction in abnormal movement generation by selectively restoring torsinA to these cells (Aim 1), decisively moving beyond the current association between these factors. We will determine if cholinergic dysfunction arises primarily from intrinsic ChI abnormalities or defects in how they respond to afferents (Aim 2), and, informed by Aims 1 and 2, will pursue translational studies (Aim 3) testing whether directly modulating the activity of surviving ChIs can suppress dystonic-like movements. This proposal is therefore highly signifiant because it will define a circuit-based model of motor dysfunction that will inform the design of targeted therapeutics.

项目总结/文摘