Glutamate in Development of Auditory Brainstem

谷氨酸在听觉脑干发育中的作用

• 批准号: 6927535
• 负责人: DEDA C GILLESPIE
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2005-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6927535
• 关键词: AMPA receptors; NMDA receptors; auditory nuclei; auditory pathways; developmental neurobiology; gamma aminobutyrate; gene expression; glutamate transporter; glycine; immunocytochemistry; laboratory rat; neural plasticity; neurotransmitter transport; olivary body; receptor expression; sound perception

DESCRIPTION (provided by applicant): The lateral superior olive (LSO), a binaural nucleus involved in sound localization, receives converging excitatory and inhibitory projections that are precisely tonotopically matched. The inhibitory projection from the MNTB is refined early in postnatal life through mechanisms that are largely unknown. It was recently found that inhibitory neurons in the MNTB-LSO projection release glutamate during the period of synaptic refinement. The vesicular glutamate transporter VGLUT3, which could support this glutamate release, is transiently expressed in the LSO during the same period and is downregulated shortly after hearing onset. This project will test the hypothesis that VGLUT3 expression in the LSO is downregulated by specific auditory experience. It also aims to test the hypothesis that different vesicular glutamate transporters specifically label the excitatory and inhibitory projections during development. The early glutamatergic transmission in the MNTB-LSO pathway is mediated in large part by postsynaptic NMDA receptors. NMDA receptors have known roles in synaptic plasticity in many systems, with different NMDA receptor subtypes playing distinct roles. Thus, an understanding of the particular NMDA receptor subtypes involved, and whether glutamate is likely to be co-released with GABA and glycine, will be necessary for further studies of glutamate's role in development of the LSO. The third arm of this proposal is to characterize basic physiology of glutamate transmission in both excitatory and inhibitory pathways, as a framework for further studies on the coordinated development of inhibitory and excitatory synapses. Conclusions from these studies will provide insight into the development of a major auditory nucleus, and may ramify beyond the auditory system to shed light on brain disorders involving abnormal inhibition, such as epilepsy and autism.

描述（由申请人提供）：外侧上橄榄（LSO）是参与声音定位的双耳核，接收精确音调匹配的会聚兴奋性和抑制性投射。 MNTB 的抑制投射在出生后早期通过很大程度上未知的机制得到完善。最近发现，MNTB-LSO 投射中的抑制性神经元在突触细化期间释放谷氨酸。囊泡谷氨酸转运蛋白 VGLUT3 可支持谷氨酸释放，在同一时期在 LSO 中短暂表达，并在听力出现后不久下调。该项目将测试 LSO 中 VGLUT3 表达因特定听觉体验而下调的假设。它还旨在检验以下假设：不同的囊泡谷氨酸转运蛋白在发育过程中专门标记兴奋性和抑制性投射。 MNTB-LSO 途径中的早期谷氨酸传递在很大程度上是由突触后 NMDA 受体介导的。 NMDA 受体在许多系统的突触可塑性中发挥着已知的作用，不同的 NMDA 受体亚型发挥着不同的作用。因此，了解所涉及的特定 NMDA 受体亚型，以及谷氨酸是否可能与 GABA 和甘氨酸共同释放，对于进一步研究谷氨酸在 LSO 发育中的作用是必要的。该提案的第三部分是描述兴奋性和抑制性途径中谷氨酸传输的基本生理学特征，作为进一步研究抑制性和兴奋性突触协调发展的框架。这些研究的结论将提供对主要听觉核发育的深入了解，并可能扩展到听觉系统之外，以揭示涉及异常抑制的大脑疾病，例如癫痫和自闭症。