Nicotinic-glutamatergic Interactions in Axonal Development

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症。这些情况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，了解这些受体在突触改变和发育中的作用可能对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变化，但突触前机制对这些过程也至关重要。在突触修饰的突触后机制中，包括突触前NMDA受体在内的突触前谷氨酸能受体被认为参与了轴突分支和钮扣形成的调节。我们的初步数据表明，轴突a7烟碱乙酰胆碱受体（nAChR）调节谷氨酸能突触前扣的位置和大小以及突触前nmdar介导的谷氨酸能传递，这表明轴突a7烟碱乙酰胆碱受体和突触前nmdar可能是介导谷氨酸能轴突突触发生和结构可塑性的内在因素和信号机制。在目前的建议中，我们将通过在发育模型和新生儿大脑中详细评估这些事件来扩展这项工作。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，以及这些事件的时间周期。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，以确定这些相互作用发生的关键时期，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，并为在特定疾病背景下解释这些结果提供基础。这将允许直接针对这些疾病进行新的调查。

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.