Rescue of cortical inhibitory synapses following developmental hearing loss

发育性听力损失后皮质抑制性突触的挽救

基本信息

批准号：
10394208
负责人：
Dan Harvey Sanes
金额：
$ 47.57万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-10 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10394208
关键词：
Abbreviations Address Adult Age Animals Auditory Auditory Perception Auditory area Baclofen Basic Science Behavioral Bilateral Bilateral Hearing Loss Brain Cells Child Childhood Clinical Research Closure by clamp Cochlea Cognitive deficits Collaborations Communication Control Animal Detection Development Earplug Enhancers Excitatory Postsynaptic Potentials GABA Receptor GABA-A Receptor Genes Genome Gerbils Goals Impairment Individual Inhibitory Synapse Injections Interneurons Learning Light Measures Mediating Methods Molecular Target Neuraxis Pathology Perception Performance Pharmaceutical Preparations Property Proteins Psychometrics Pyramidal Cells Research Research Support Risk Role Saline Sensory Slice Synapses System Testing Transfection Viral Vector auditory processing behavior test calmodulin-dependent protein kinase II childhood hearing loss design developmental disease gamma-Aminobutyric Acid gephyrin hearing impairment high throughput screening hippocampal pyramidal neuron improved innovation normal hearing optogenetics permanent hearing loss postnatal postsynaptic promoter protein transport receptor receptor expression scaffold skills synaptic function synaptic inhibition transmission process vector zolpidem

项目摘要

PROJECT SUMMARY Hearing loss (HL) is the most prevalent childhood sensory impairment, posing a risk for deficits in aural communication. Moreover, these deficits can persevere even after normal audibility returns, suggesting that developmental HL permanently impairs central synapse function which compromises auditory perception. In fact, transient HL in gerbils induces perceptual deficits that are well-correlated with reduced inhibitory synaptic strength in auditory cortex (ACx) (Caras & Sanes, 2015; Mowery et al. 2015, 2016). Furthermore, this deficit is due to loss of both GABAA and GABAB receptor-mediated inhibition. Therefore, this proposal explores a causal relationship between weakened inhibition and perceptual deficits. Our core hypothesis is that developmental hearing loss induces a reduction of both postsynaptic GABAA- and GABAB receptor-mediated inhibition within auditory cortex, thereby causing perceptual deficits. Three aims test predictions that emerge from this hypothesis: Aim 1 tests the prediction that GABAA- and GABAB receptor-mediated inhibitory postsynaptic potentials (IPSP) must each be rescued to regain normal inhibitory strength following HL. Gerbils will be reared with transient bilateral HL (earplugs) from postnatal (P) days 11-23, and receive daily injections of a GABAergic enhancer during this period. Animals will then be reared to adulthood (>P86) with normal hearing, and an optogenetic approach will be used to assess GABAA and GABAB IPSPs in brain slices. To assess off- target effects, both EPSPs and discharge properties will be measured. Comparisons will be made to vehicle- treated HL and control animals. Aim 2 tests the prediction that HL-induced inhibitory weakening is intrinsic to ACx pyramidal cells. Gerbils will be reared with HL from P11-23, and ACx layer 2/3 pyramidal cells will then be transfected with genes that encode GABA receptor subunits or trafficking proteins, each obtained from the newly available gerbil genome sequence. As in Aim 1, optogenetic assessment of IPSPs, EPSPs, and discharge properties will be obtained from adult ACx. Aim 3 tests the prediction that perceptual deficits can be restored by rescuing ACx synaptic inhibition. Gerbils will be reared with HL from P11-23 and receive either: daily injections an effective GABA enhancer (Aim 1), or ACx transfection with an effective vector (Aim 2). Animals will then be tested on an amplitude modulation (AM) detection task to obtain psychometric thresholds. To determine whether perception correlates with inhibitory strength, an optogenetic assessment of IPSPs will be obtained from the same animals. Innovations in this proposal are: (i) collaborations to sequence the gerbil genome and to equip vectors with gerbil-specific genes, (ii) a high throughput assay of adult ACx synapse function using optogenetics, and (iii) an emphasis on the role of GABAB receptors in developmental disorders. Together, the significance of this proposal is to identify and remediate a CNS mechanism that contributes to the perceptual deficits that attend childhood HL. If successful, the project will provide one explanation for the educational barriers that persist in children with HL that is separate from cochlear pathology.

项目摘要听力损失（HL）是最普遍的儿童感觉障碍，构成听觉缺陷的风险沟通。此外，即使在正常的听觉返回后，这些缺陷也可以坚持不懈，表明发育HL永久损害损害听觉感知的中央突触功能。在事实，沙鼠中的瞬态HL诱发了与抑制性突触相关的感知缺陷听觉皮层的力量（ACX）（Caras＆Sanes，2015; Mowery et al。2015，2016）。此外，这种赤字是由于GABAA和GABAB受体介导的抑制作用的丧失。因此，该提案探讨了因果关系抑制和感知缺陷之间的关系之间的关系。我们的核心假设是发展听力损失诱导突触后GABAA-和GABAB受体介导的抑制作用减少听觉皮层，从而导致感知缺陷。从中出现的三个目标测试预测假设：目标1测试了GABAA和GABAB受体介导的抑制性突触的预测必须救出电位（IPSP），以恢复HL之后的正常抑制强度。沙鼠将饲养与产后（P）第11-23天的瞬时双侧HL（耳塞），并每天注射在此期间，GABA能增强剂。然后，动物将在正常的听力下饲养到成年（> p86），并且一种光遗传学方法将用于评估脑切片中的GABAA和GABAB IPSP。评估非目标效应，EPSP和放电性能将被测量。将与车辆进行比较 - 治疗的HL和对照动物。 AIM 2测试HL诱导的抑制性削弱是固有的预测 ACX锥体细胞。沙鼠将用P11-23的HL饲养，然后ACX层2/3锥体细胞将是用编码GABA受体亚基或运输蛋白的基因转染，每个基因从新可用的沙鼠基因组序列。与AIM 1一样，IPSP，EPSP和排出特性将从成人ACX获得。 AIM 3测试可感知缺陷的预测通过挽救ACX突触抑制来恢复。 Gerbils将从P11-23中饲养HL，并接收：每天注射有效的GABA增强子（AIM 1）或有效向量转染ACX转染（AIM 2）。然后，将在振幅调制（AM）检测任务上测试动物以获得心理测量阈值。为了确定感知是否与抑制强度相关，IPSP的光遗传学评估将会可以从同一动物获得。该提案中的创新是：（i）协作对杰尔比尔进行排序基因组和为载体配备沙鼠特异性基因，（ii）成人ACX突触的高吞吐量测定使用光遗传学的功能，（iii）强调GABAB受体在发育障碍中的作用。共同，该提案的意义是识别和补救有助于的中枢神经系统机制参加童年HL的感知缺陷。如果成功，该项目将为与人工耳蜗病理学分开的HL儿童的教育障碍。