Glutamate release at inhibitory synapses in developing auditory system

听觉系统发育过程中抑制性突触的谷氨酸释放

• 批准号: 7275675
• 负责人: Abigail Susan Kalmbach
• 金额: $ 4.1万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7275675
• 关键词: AMPA Receptors; Address; Age; Area; Arts; Auditory; Auditory system; Automobile Driving; Biological; Biological Models; Brain; Brain Stem; Calcium; Calcium Channel; Cell Nucleus; Cells; Chromosome Pairing; Class; Communication; Communication impairment; Dendrites; Development; Disease; Distal; Dyslexia; Fellowship; Generations; Glutamate Receptor; Glutamates; Glycine; Goals; Hearing; Human; Image; Individual; Inhibitory Synapse; Laboratories; Language; Language Disorders; Lateral; Lead; Location; Maps; Medial; Mediating; Metabotropic Glutamate Receptors; Mus; N-Methyl-D-Aspartate Receptors; Names; Neonatal; Neurons; Neurotransmitters; Olives - dietary; Pathway interactions; Phenotype; Photons; Physiological; Process; Research; Resolution; Role; Route; Series; Slice; Sound Localization; Synapses; System; Techniques; Testing; Thinking; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; base; day; disability; gamma-Aminobutyric Acid; inhibitory neuron; insight; metabotropic glutamate receptor type 1; neural circuit; neuronal cell body; patch clamp; postnatal; postsynaptic; receptor; research study; response; sensory system; trapezoid body; voltage

DESCRIPTION (provided by applicant): The long term goal of this research is to provide understanding of the rules and mechanisms by which auditory circuits in the developing mammalian brain become established and functionally optimized. Proposed experiments are aimed to provide more insight into the mechanisms by which an inhibitory sound localization pathway, the glycinergic pathway from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO) becomes topographically refined. Previous studies demonstrated that, during the period of topographic refinement, individual synapses in the developing MNTB-LSO pathway not only release the inhibitory neurotransmitters glycine and GABA, but also release the excitatory transmitter glutamate. The specific aims of the proposed application are (a) to investigate how glutamate co-release and postsynaptic glutamate receptors contribute to the generation of postsynaptic calcium responses in LSO dendrites, and (b) test the hypothesis that MNTB-LSO synapses are organized on a subcellular level according to their functional neurotransmitter phenotype. These aims are addressed using a combination of 2-photon calcium imaging and whole-cell patch clamp recordings applied to brainstem slices from neonatal mice. The results from proposed experiments will be important for better understanding normal and abnormal auditory circuit development and thus may provide insights into the biological basis of human communication disorders, such as language disabilities and dyslexia that are thought to arise from abnormal development. Summery in lay language: Anatomical and functional fine-tuning of immature brain circuits are important milestones for the normal development of hearing. Proposed research plans to apply state-of-the-art physiological techniques to investigate mechanism of neuronal communication in a mouse sound localization circuit. Results from these studies may provide better understanding of the biological basis that underlie auditory disorders including language disabilities and dyslexia which ultimately can lead to new strategies of alleviating or curing these disabilities.

描述（由申请人提供）：本研究的长期目标是提供对规则和机制的理解，通过这些规则和机制，发育中的哺乳动物大脑中的听觉回路得以建立和功能优化。提出的实验旨在提供更多的洞察机制，通过该机制，抑制性声音定位途径，从内侧核的斜方体（MNTB）的甘氨酸能通路的外侧上级橄榄（LSO）变得地形细化。先前的研究表明，在地形细化期间，发育中的MNTB-LSO通路中的单个突触不仅释放抑制性神经递质甘氨酸和GABA，而且还释放兴奋性递质谷氨酸。所提出的应用的具体目的是（a）研究谷氨酸共释放和突触后谷氨酸受体如何有助于LSO树突中突触后钙响应的产生，以及（B）测试MNTB-LSO突触根据其功能性神经递质表型在亚细胞水平上组织的假设。这些目标是解决使用的组合，2-光子钙成像和全细胞膜片钳记录适用于从新生小鼠脑干切片。从拟议的实验结果将是重要的，更好地了解正常和异常的听觉回路的发展，从而可能提供洞察人类沟通障碍的生物学基础，如语言障碍和诵读困难，被认为是从异常的发展。通俗语言总结：未成熟大脑回路的解剖和功能微调是听力正常发育的重要里程碑。建议的研究计划，应用最先进的生理技术，以调查机制的神经元通信在小鼠的声音定位电路。这些研究的结果可能会提供更好的理解的生物学基础，包括语言障碍和阅读障碍，最终可以导致新的战略，减轻或治愈这些残疾的听觉障碍。