Proteolytic Regulation of Inhibitory Circuits to Gate Cortical Plasticity

抑制电路的蛋白水解调节控制皮质可塑性

• 批准号: 9187806
• 负责人: Hirofumi Morishita
• 金额: $ 42.07万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9187806
• 关键词: Acute; Adult; Affect; Alteplase; Amblyopia; Autistic Disorder; Blindness; Brain; Brain Diseases; Brain Injuries; Cells; Disease; Electrophysiology (science); Excision; Extracellular Matrix Proteins; Gene Expression; Genetic; Human; Injury; Interneurons; Intervention; Life; Mediating; Modeling; Molecular; Mus; Neurodevelopmental Disorder; Neurons; Ocular Dominance; Parvalbumins; Peptide Hydrolases; Pharmacogenetics; Phase; Pilot Projects; Plasticizers; Play; Population; Positioning Attribute; Pyramidal Cells; Recovery; Recovery of Function; Regulation of Proteolysis; Role; Sensory; Series; Serine; Slice; Somatostatin; Source; Synapses; Techniques; Testing; Therapeutic; Varicosity; Viral; Visual; Visual Acuity; Visual Cortex; Whole-Cell Recordings; area striata; cell type; critical developmental period; critical period; deprivation; experience; extracellular; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; in vivo; infancy; inhibitor/antagonist; injury and repair; knock-down; monocular deprivation; neuroserpin; novel; optogenetics; overexpression; patch clamp; public health relevance; response; therapeutic evaluation

 DESCRIPTION (provided by applicant): Experience-dependent brain plasticity is heightened during developmental critical periods but declines into adulthood, posing a major challenge to recovery of function following injury or disease later in life. A dominant model of critical period plasticity is the change in ocular dominance of neurons in primary visual cortex following monocular deprivation. Recent studies suggest that experience-dependent plasticity of Parvalbumin positive (PV-) GABA interneurons in visual cortex plays a key role in triggering ocular dominance plasticity during the critical period. Importantly, such rapid plasticity of PV cells is limited to the critical period and is not observed in adults. Our pilot study further showd that another major subtype of interneurons expressing Somatostatin (SST) can also modulate ocular dominance plasticity in the adult. These studies underscore the novel role of interneurons in rapidly gating cortical plasticity in adult visual cortex. However, the molecular and circuit mechanisms that limit the rapid plasticity triggered by interneurons in the adult are totally unknown. This proposal deals with this open question to provide new mechanisms of the initial phase of plasticity to effectively re-trigger plastic windows for recovery of cortical function in adults. We turn to proteolytic regulation because tissue plasminogen activator (tPA), a major protease in the brain, is known to rapidly elevate during only critical period but not in adulthood to mediate plasticity. Our preliminary study found that the removal of one endogenous tPA inhibitors called Neuroserpin, enriched in adult PV- and SST-cells, leads to a series of experience-dependent rapid changes to unmask plasticity in adult visual cortex. By combining in vivo extracellular recordings, patch-clamp electrophysiology with optogenetics, pharmacogenetics, and cell-type specific gain/loss of gene expression through genetic and viral techniques in vivo, we will test our hypothesis that proteolytic regulation by an endogenous serine inhibitor, Neuroserpin, gates the sensitivity of PV- and SST- interneurons to rapidly trigger visual cortex plasticity and recovery in adulthood. Proteolytic regulation of rapid plasticty associated with PV-interneurons and SST-interneurons will be examined in Aim1 and Aim2 respectively. In Aim3, therapeutic potential for recovery from amblyopia by targeting Neuroserpin in interneurons will be tested. Successful completion of this project will illuminate new molecular mechanism that gates the initial cascade triggering cortical plasticity, which will have direct implications for Amblyopia, a condition with limited adult-applicable cure affecting 2-5% of the human population, but also for brain injury repair, sensory recovery.

 描述（由申请人提供）：经验依赖性大脑可塑性在发育关键期提高，但在成年期下降，对以后生活中受伤或疾病后的功能恢复构成重大挑战。关键期的主导模型 可塑性是单眼剥夺后初级视皮层神经元的眼优势的变化。最近的研究表明，视皮层小白蛋白阳性（PV-）GABA中间神经元的经验依赖性可塑性在关键期触发眼优势可塑性中起着关键作用。重要的是，PV细胞的这种快速可塑性仅限于关键期，并且在成人中未观察到。我们的初步研究进一步表明，另一种主要的表达生长抑素（SST）的中间神经元亚型也可以调节成年人的眼优势可塑性。这些研究强调了中间神经元在成人视皮层快速门控皮层可塑性中的新作用。然而，限制成人中间神经元触发快速可塑性的分子和电路机制是完全未知的。本研究旨在解决这一问题，为可塑性的初始阶段提供新的机制，以有效地重新触发成年人大脑皮层功能恢复的塑料窗。 我们转向蛋白水解调节，因为组织纤溶酶原激活物（tPA），一种脑中的主要蛋白酶，已知仅在关键时期而不是在成年期迅速升高 来调节可塑性。我们的初步研究发现，去除一种内源性tPA抑制剂，称为Neuroserpin，在成人PV-和SST-细胞中富集，导致一系列经验依赖性的快速变化，以揭示成人视觉皮层的可塑性。 通过结合体内细胞外记录，膜片钳电生理学与光遗传学，药物遗传学，和细胞类型特异性增益/损失的基因表达，通过遗传和病毒技术在体内，我们将测试我们的假设，蛋白水解调节的内源性丝氨酸抑制剂，Neuroserpin，门的敏感性PV-和SST- interneurons快速触发视觉皮层可塑性和恢复成年。将分别在Aim 1和Aim 2中检查与PV-中间神经元和SST-中间神经元相关的快速可塑性的蛋白水解调节。在Aim 3中，将测试通过靶向中间神经元中的Neuroserpin从弱视恢复的治疗潜力。 该项目的成功完成将阐明新的分子机制，该机制开启了触发皮层可塑性的初始级联反应，这将对弱视产生直接影响，弱视是一种影响2-5%人口的成人适用治疗有限的疾病，但也适用于脑损伤修复，感觉恢复。