Nicotinic-glutamatergic Interactions in Axonal Development

轴突发育中的烟碱-谷氨酸相互作用

• 批准号: 8269860
• 负责人: DAVID ROBINSON LYNCH
• 金额: $ 20.94万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269860
• 关键词: Affect; Alzheimer' s Disease; Animals; Attention; Axon; Brain; Choline; Cholinergic Receptors; Complement; Data; Development; Developmental Process; Disease; Disease model; Down Syndrome; Event; Excitatory Synapse; Glutamate Receptor; Glutamates; Hippocampus (Brain); Intrinsic factor; Investigation; Knockout Mice; Learning; Location; Mediating; Memory; Mental disorders; Modeling; Modification; Morphology; N-Methyl-D-Aspartate Receptors; Neonatal; Neuronal Plasticity; Neurons; Neuropil; Neurotransmitter Receptor; Newborn Animals; Nicotine; Nicotinic Receptors; Physiological; Presynaptic Terminals; Process; Property; Regulation; Role; Schizophrenia; Series; Signal Transduction; Slice; Small Interfering RNA; Structure; Synapses; Synaptic plasticity; System; Vertebral column; Work; addiction; base; cholinergic; critical period; model development; nervous system disorder; neural circuit; neuron development; neuronal growth; novel therapeutic intervention; postnatal; postsynaptic; presynaptic; receptor; research study; synaptogenesis; transmission process

DESCRIPTION (provided by applicant): A variety of neurological and psychiatric disorders are associated with alterations in synaptic plasticity, including Alzheimer's disease, schizophrenia, and Down syndrome. Each of these conditions has also been suggested to involve pharmacological modulation by multiple neurotransmitter receptors, including both the N-methyl D-aspartate receptor (NMDA) and cholinergic nicotinic receptors, particularly the a7 receptor. Understanding the role of such receptors in synaptic alterations and development may thus be crucial for the development of novel therapeutic approaches. The cellular basis for neural plasticity that underlies learning and memory involves a combination of functional and structural alterations in neurons and synapses. While much attention has focused on N- methyl-D-aspartate receptor (NMDAR)-dependent postsynaptic mechanisms involved in long-term change, presynaptic mechanisms are also crucial to such these processes. As seen in postsynaptic mechanisms of synaptic modification, presynaptic glutamatergic receptors including presynaptic NMDA receptors have been proposed to be involved in the regulation of axonal branching and bouton formation. Our preliminary data demonstrate that the axonal a7 nicotinic acetylcholine receptors (nAChR) modulate the location and size of glutamatergic presynaptic boutons and presynaptic NMDAR-mediated glutamatergic transmission in cortical cultures, suggesting that the axonal a7 nAChR and presynaptic NMDARs may be intrinsic factors and signaling mechanisms that mediate synaptogenesis and structural plasticity of glutamatergic axons. In the present proposal, we will extend this work through detailed assessment of these events in models of development and in neonatal brain. This will also allow us to ascertain the role of nAChR-NMDAR interactions in synaptogenesis and structural plasticity, and the temporal periods for such events. We will begin with complete definition of the pharmacological mechanism underlying the presynaptic interactions of a7 and NMDAR. We will then assess the development course of these events to define the critical period during which such interactions occur using neuronal cultures, hippocampal slice cultures and neonatal animals. Collectively these experiments will allow us to identify the mechanisms that mediate the presynaptic interactions of nicotinic and glutamatergic systems, and provide a basis for interpreting these results in the contexts of specific disorders. This will allow new investigations directly targeting these diseases.

描述（由申请人提供）：多种神经和精神疾病与突触可塑性的改变有关，包括阿尔茨海默病、精神分裂症和唐氏综合征。这些病症中的每一种也被认为涉及通过多种神经递质受体的药理学调节，所述神经递质受体包括N-甲基D-天冬氨酸受体（NMDA）和胆碱能烟碱受体，特别是α 7受体。因此，了解这些受体在突触改变和发育中的作用对于开发新的治疗方法至关重要。作为学习和记忆基础的神经可塑性的细胞基础涉及神经元和突触的功能和结构改变的组合。虽然许多注意力集中在N-甲基-D-天冬氨酸受体（NMDAR）依赖的突触后机制参与长期的变化，突触前机制也是至关重要的这些过程。如在突触修饰的突触后机制中所见，已经提出包括突触前NMDA受体的突触前神经递质能受体参与轴突分支和终扣形成的调节。我们的初步数据表明，轴突α 7烟碱乙酰胆碱受体（nAChR）调节的位置和大小的突触前终扣和突触前NMDAR介导的突触传递皮层文化中的突触能，这表明轴突α 7 nAChR和突触前NMDAR可能是内在的因素和信号机制，介导突触发生和结构可塑性的突触能轴突。在本提案中，我们将通过详细评估这些事件在模型中的发展和新生儿大脑中扩展这项工作。这也将使我们能够确定nAChR-NMDAR相互作用在突触发生和结构可塑性中的作用，以及这些事件的时间周期。我们将开始与α 7和NMDAR的突触前相互作用的药理学机制的完整定义。然后，我们将评估这些事件的发展过程，以确定关键时期，在此期间，这种相互作用发生使用神经元培养，海马切片培养和新生动物。总的来说，这些实验将使我们能够确定的机制，介导的突触前相互作用的烟碱和nitamatergic系统，并提供了一个基础，解释这些结果的背景下，特定的疾病。这将允许直接针对这些疾病进行新的调查。