Nicotinic-glutamatergic Interactions in Axonal Development

轴突发育中的烟碱-谷氨酸相互作用

• 批准号: 8189649
• 负责人: DAVID ROBINSON LYNCH
• 金额: $ 23.44万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8189649
• 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. PUBLIC HEALTH RELEVANCE: This proposal will investigate interactions between the nicotinic acetyl choline receptors and glutamate receptors. We hypothesize that these mediate developmental processes and neuronal growth. This potentially will have major impact on understanding of nicotine exposure and addiction, Alzheimer's disease and schizophrenia.

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相关，包括阿尔茨海默病、精神分裂症和唐氏综合症。这些病症中的每一种也被认为涉及多种神经递质受体的药理调节，包括 N-甲基 D-天冬氨酸受体 (NMDA) 和胆碱能烟碱受体，特别是 a7 受体。因此，了解此类受体在突触改变和发育中的作用可能对于开发新的治疗方法至关重要。学习和记忆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。虽然很多注意力集中在参与长期变化的 N-甲基-D-天冬氨酸受体 (NMDAR) 依赖性突触后机制，但突触前机制对于这些过程也至关重要。正如在突触修饰的突触后机制中所见，突触前谷氨酸能受体（包括突触前 NMDA 受体）已被认为参与轴突分支和布顿形成的调节。我们的初步数据表明，轴突a7烟碱乙酰胆碱受体（nAChR）调节皮质培养物中谷氨酸突触前开关和突触前NMDAR介导的谷氨酸传递的位置和大小，这表明轴突a7 nAChR和突触前NMDAR可能是介导的内在因素和信号机制 谷氨酸轴突的突触发生和结构可塑性。在本提案中，我们将通过对发育模型和新生儿大脑中的这些事件进行详细评估来扩展这项工作。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，以及此类事件的时间周期。我们将从 a7 和 NMDAR 突触前相互作用的药理学机制的完整定义开始。然后，我们将评估这些事件的发展过程，以确定使用神经元培养物、海马切片培养物和新生动物发生此类相互作用的关键时期。总的来说，这些实验将使我们能够确定介导烟碱和谷氨酸系统突触前相互作用的机制，并为在特定疾病的背景下解释这些结果提供基础。这将使直接针对这些疾病的新研究成为可能。 公共健康相关性：该提案将研究烟碱乙酰胆碱受体和谷氨酸受体之间的相互作用。我们假设这些介导发育过程和神经元生长。这可能会对了解尼古丁暴露和成瘾、阿尔茨海默病和精神分裂症产生重大影响。