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）：多种神经系统和精神疾病与突触可塑性的改变有关，包括阿尔茨海默氏病，精神分裂症和唐氏综合症。这些条件中的每一个还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，尤其是A7受体。因此，了解此类受体在突触改变和发育中的作用对于新型治疗方法的发展可能至关重要。基于学习和记忆的神经可塑性的细胞基础涉及神经元和突触中功能和结构改变的结合。尽管很多关注集中在N-甲基-D-天冬氨酸受体（NMDAR）依赖性的突触后机制中涉及长期变化，但突触前机制对于此类过程也至关重要。如突触修饰的突触后机制所示，已经提出突触前谷氨酸能受体在内，包括突触前NMDA受体受体参与轴突分支和胸骨形成的调节。我们的初步数据表明，轴突A7烟碱乙酰胆碱受体（NACHR）调节了谷氨酸能 - 突触前的胸子的位置和大小，以及突触前NMDAR介导的谷氨酰胺介导的皮质培养物中的谷氨酸膜的传播，这表明轴突含量是轴突nachr的机制，并可能内部地定位为nachr anchr和Pristion Nmapticnmapticnmants ands ands and anmdass and s.谷氨酸能轴突的突触发生和结构可塑性。在本提案中，我们将通过对开发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。我们将从对A7和NMDAR的突触前相互作用的基础的药理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，以定义使用神经元培养物，海马切片培养物和新生儿动物发生这种相互作用的关键时期。这些实验共同使我们能够确定介导烟碱和谷氨酸能系统的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了基础。这将允许直接针对这些疾病的新调查。