Modulation of Exocytosis and Excitability in Mature Auditory Brainstem Neurons

项目总结 本行政副刊的主要目的是确定神经元兴奋性的变化和 阿尔茨海默病(AD)和老年期间哺乳动物听觉脑干内的突触强度 相关性听力损失(ARHL)。我们将使用成熟的转基因小鼠品系和品系作为实验 AD和ARHL的模型。正如我们的父母R01拨款所建议的那样，我们将研究 听性脑干：位于斜方体内侧核(MNTB)内的大突触的花冠。 外侧上橄榄(LSO)的小环型甘氨酸能和谷氨酸能突触。这些突触 是计算高频声源定位的听觉脑干电路的关键。双耳 听觉是哺乳动物声源定位的重要机制。它还提供了 从背景噪声中过滤重要的听觉输入的关键手段。不能辨别声音 声源定位或在嘈杂环境中感知语音是听力损失的常见形式，尤其是在老年人 个人。听力受损也有助于对患有ARHL的个人进行社会隔离，这是 减少他们的认知刺激，加重甚至导致痴呆症的情况。长期目标是 测定动物MNTB和LSO突触的神经元兴奋性和生物物理特性 经历AD和ARHL进展的不同阶段。我们将进行单细胞膜片钳 成年和老龄小鼠不同发育阶段脑干脑片的电生理记录 对照组和阿尔茨海默病模型的成年期和衰老。我们的初步数据显示，有几个基本方面 脑干突触的数量和神经元的兴奋性在年轻成年小鼠中已经发生了显着的变化(三种 一个月大)，在严重的AD症状明显显现之前。在成年期和衰老期间，进一步的突触 并观察到兴奋性的变化，有时是相反的方向。因此，我们建议研究 AD和AD大鼠脑内神经元的突触强度、短时突触可塑性和神经元兴奋性 ARHL小鼠模型。第一个假设是LSO和MNTB神经元的内在兴奋性是 阿尔茨海默病和衰老小鼠模型的显著降低使兴奋性突触后电位更难 (EPSPS)达到峰值阈值。第二个假说是AD和衰老中的突触强度 由于突触囊泡释放概率和/或改变，脑干突触发生显著变化 突触小泡可释放池大小的变化。研究结果将提供新的见解，揭示 导致青年AD病理和听力障碍及衰老的几个潜在机制 听觉神经元和突触。因此，拟议的研究将极大地刺激额外的活动，从而导致 哺乳动物大脑中阿尔茨海默病和听力损失的根本原因的重大进展。

PROJECT SUMMARY The major goal of this Administrative Supplement is to determine the changes in neuronal excitability and synaptic strength within the mammalian auditory brainstem during Alzheimer’s disease (AD) and during age related hearing loss (ARHL). We will use well established transgenic mouse lines and strains as experimental models for AD and ARHL. As proposed in our parent R01 grant, we will study two specialized synapses in the auditory brainstem: the large calyx of Held synapse in the medial nucleus of the trapezoid body (MNTB) and the small bouton-type glycinergic and glutamatergic synapses of the lateral superior olive (LSO). These synapses are pivotal for the auditory brainstem circuits that compute high frequency sound source localization. Binaural hearing constitutes an important mechanism for localizing sound sources in mammalian species. It also provides a critical means for filtering important auditory inputs from background noise. The inability to distinguish sound source location or perceive speech in noisy environments are common forms of hearing loss, especially in elderly individuals. Impaired hearing also contributes for social isolation of individulas who suffer from ARHL, which reduces their cognitive stimulation, aggravating or even leading to instances of dementia. The long-term goal is to determine the neuronal excitability and biophysical properties of the MNTB and LSO synapses as animals experience different stages of AD and ARHL progression. We will perform single cell patch clamp electrophysiology recordings in mouse brainstem slices from adult and aging mice at different stages of adulthood and aging in both control and AD models. Our preliminary data show that several fundamental aspects of brainstem synapses and neuronal excitability are significantly changed already in young adult mice (three month old) before severe symptoms of AD become clearly manifest. During adulthood and aging, further synaptic and excitability changes are observed, sometimes in the opposite direction. We thus propose to study the synaptic strength, short-term synaptic plasticity and neuronal excitability of neurons from the brains of AD and ARHL mouse models. The first hypothesis is that the intrinsic excitability of LSO and MNTB neurons is significantly reduced in AD and aging mice models making it harder for excitatory postsynaptic potentials (EPSPs) to reach spike threshold. The second hypothesis is that the synaptic strength in AD and aging brainstem synapses changes significantly because of changes in synaptic vesicle release probability and/or changes in the readily releasable pool size of synaptic vesicles. The results will provide novel insights that reveal several underlying mechanisms responsible for AD pathology and hearing deficits in young adults and aging auditory neurons and synapses. The proposed studies will thus greatly stimulate additional activity leading to significant progress on the fundamental causes of AD dementia and hearing loss in the mammalian brain.