Disrupted auditory cortical plasticity and behavior in a model of Rett syndrome

 描述(由申请人提供)：自闭症谱系障碍(ASD)的普遍特征是语言的感知和产生能力受损，以及普遍存在的社会行为缺陷。然而，将无序的分子和发育事件与改变的行为联系起来的体内电路的变化在很大程度上是未知的。因此，这项建议的目标是：1)识别支持发声感知的抑制性神经元回路2)确定它们在Rett综合征啮齿动物模型中是如何受损的3)使用新的遗传和药理学策略修复抑制回路。为了实现这些目标，我们建议使用新的行为分析、遗传方法和电生理学的组合。利用这些工具，我们可以观察特定抑制回路的可塑性，评估干扰这些回路的神经和行为后果，并最终通过修复这些回路来恢复行为功能。在我们的初步数据中，我们描述了一种简单、可靠和与行为学相关的对Rett综合征模型(只携带一个MeCP2基因副本的小鼠)母体行为的分析。我们的测试结果揭示了母体社会学习的一个严重缺陷，我们假设这与对幼崽发声的不良感知有关。事实上，我们通过以下方式将收集行为与听觉皮质的功能和可塑性联系起来：1)听觉皮质中MeCP2的表达是熟练的母体行为所必需的。2)听觉皮层神经元对发声刺激的抑制反应可塑性受损。3)免疫组织化学标记物数据反映了听觉皮质抑制网络对母亲经历的反应异常成熟。关键是，HETS的特征是周围神经网(PNN)的表达增强，这种结构与抑制网络密切相关，被认为限制了可塑性。4)对GABA能抑制功能的“基因拯救”操作可减轻PNN表达的升高，并显著恢复正常的行为表现。5)在母亲经历之前，选择性地抑制听觉皮质中的PNN，也足以恢复母亲的学习。我们的目标是识别控制声音感知的特定听觉皮质回路，以确定体内功能 MeCP2杂合性在这些电路中的后果，并通过对这些电路的遗传操作来挽救电路的功能和行为。通过实现这些目标，我们将在Rett综合征小鼠模型中的分子和电路病理与社交沟通受损之间建立关键联系，并可能确定用于治疗干预的候选电路靶点。

 DESCRIPTION (provided by applicant): Impaired perception and production of language, as well as deficits in social behavior generally, are pervasive features among the autism spectrum disorders (ASD). However, the changes to in vivo circuitry that connect disordered molecular and developmental events to altered behavior are largely unknown. Therefore, the goals of this proposal are: 1) To identify inhibitory neuronal circuits that support vocal perception 2) To determine how they are impaired in a rodent model of Rett syndrome 3) To repair the inhibitory circuitry using novel genetic and pharmacological strategies. To achieve these goals, we propose to use a combination of novel behavioral assays, genetic methods, and electrophysiology. With these tools, we can observe plasticity in specific inhibitory circuits, assess the neural and behavioral consequences of perturbing these circuits, and ultimately restore behavioral function by repairing those circuits. In our preliminary data, we describe a simple, robust and ethologically relevant assay of maternal behavior in a model of Rett syndrome (mice carrying only one copy of the gene MeCP2 - `hets'). Our results with this assay reveal a profound deficit of maternal social learning in hets that we hypothesize is related to poor perception of pup vocalizations. Indeed, we link gathering behavior to function and plasticity of the auditory cortex by showing that: 1) MeCP2 expression in the auditory cortex is necessary for proficient maternal behavior. 2) Auditory cortical neurons in hets exhibit impaired plasticity of inhibitory responses to vocal stimuli. 3) Immunohistochemical marker data reflect dysregulated maturation of auditory cortical inhibitory networks in response to maternal experience. Crucially, the hets are characterized by enhanced expression of perineuronal nets (PNNs), structures that closely associate with inhibitory networks and are thought to limit plasticity. 4) A `genetic rescue' manipulation of GABAergic inhibitory function relieves the elevated PNN expression, and remarkably restores normal behavioral performance. 5) Pharmacological inhibition of PNNs selectively in the auditory cortex prior to maternal experience is sufficient to restore maternal learning as well. Our objectives are to identify specific auditory cortical circuits governing vocal perception, to determine the in vivo functional consequences of MeCP2 heterozygosity in these circuits, and to rescue circuit function and behavior with a genetic manipulation of these circuits. By achieving these goals, we will forge crucial links between molecular and circuit pathologies and impaired social communication in the Rett syndrome mouse model, and we will potentially identify candidate circuit targets for therapeutic intervention.