Glutamate release at inhibitory synapses in developing auditory system

描述(申请人提供)：这项研究的长期目标是提供对发育中的哺乳动物大脑中听觉回路建立和功能优化的规则和机制的理解。拟议的实验旨在更深入地了解从斜方体内侧核(MNTB)到外侧上橄榄(LSO)的抑制性声音定位通路--甘氨酸能通路--变得地形化的机制。以往的研究表明，在地形图精细化期间，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，还释放兴奋性递质谷氨酸。该应用的具体目的是(A)研究谷氨酸共释放和突触后谷氨酸受体如何在LSO树突中参与突触后钙反应的产生，以及(B)检验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。这些目标是通过结合应用于新生小鼠脑干切片的双光子钙成像和全细胞膜片钳记录来实现的。拟议中的实验结果对于更好地理解正常和异常的听觉回路发育将是重要的，从而可能为人类沟通障碍的生物学基础提供见解，例如语言障碍和阅读障碍，这些被认为是由异常发育引起的。外行语言总结：未成熟大脑回路的解剖和功能微调是听力正常发展的重要里程碑。拟议的研究计划应用最先进的生理学技术来研究小鼠声音定位电路中神经元通信的机制。这些研究的结果可能会更好地理解包括语言障碍和阅读障碍在内的听觉障碍的生物学基础，最终可能导致缓解或治疗这些障碍的新策略。

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.