Neuregulin/Alpha7nAChR Signaling, the GABAergic Switch and Neurodevelopmental Risk: Mechanisms of Gestational Choline Supplementation.

项目摘要 在早期脑发育过程中，由于逆氯梯度，GABA是主要的兴奋性神经递质 通过氯共转运蛋白基因NKCC 1和KCC 2介导。通过烟碱受体传递信号， a7 nAChR是正常神经发育所必需的GABA兴奋/抑制[E/I]转变的关键驱动因素。 脑中GABA能神经传递和E/I平衡的功能性成熟障碍与脑内GABA能神经传递和E/I平衡的异常有关。 在一些神经发育障碍（NDD）的发病机制中，包括自闭症谱系障碍（ASD）。 最近，我们的研究已经确定了Neuregulin 1基因启动子rs6994992的功能多态性， 这与一种新的NRG 1亚型（NRG 1-IV）的脑转录升高有关，更重要的是， 人类大脑中的α 7 nAChR水平较低。通过α 7 nAChR的信号传导是GABA的关键驱动因素。 兴奋性/抑制性（E/I）转换，通过氯转运蛋白NKCC 1和KCC 2介导，也是已知的 遗传风险因素的几个NDD，特别是ASD，在15q13.3微缺失综合征的形式。在啮齿类动物中， α 7 nAChR敲低阻止了这种转换，导致GABA能超极化的异常成熟， NRG 1是α 7 nAChRs的关键调节因子; NRG 1-IV的具体作用尚不清楚。在人体研究中，rs6994992 与人类认知、感觉处理和焦虑行为有关，我们实验室的数据表明， 携带T等位基因的婴儿感觉加工减弱，与母亲妊娠期饮食的相互作用 胆碱补充剂胆碱是一种α 7 nAChR激动剂，是一种新的产前营养补充策略 改善儿童行为和早期大脑发育。总而言之，这一目标 多学科的建议是一个新的生物学途径连接NRG 1的发展特征， 利用一种新的转基因小鼠（NRG 1-NKCC 2），研究了α 7 nAChR和NKCC 1/KCC 2在调节E/I平衡成熟中的作用。 IVtgNSE-tTA）基因修饰以在脑中表达人NRG 1-IV， 接近。我们将测试两个主要假设。NRG 1-IV过表达导致非典型性成熟， 新皮质GABA能信号和E/I皮质平衡，通过减少α 7 nAChR和发育介导 氯共转运蛋白NKCC 1和KCC 2的表达和2）。产前刺激α 7 nAChR，通过 膳食胆碱补充剂，将纠正开关的发展，改善成人E/I皮质失衡， 通过a7 nAChR机制与几种NDD相关的神经行为结果。这项研究将改善 我们对典型和非典型发育的基本机制的了解与一个关键的信号通路有关， 参与了几个NDD，特别是ASD，并为患有ASD的人确定新的治疗/干预方法。 发育障碍

Project Summary During early brain development, GABA is the main excitatory neurotransmitter due to a reverse chloride gradient mediated via the chloride co-transporter genes NKCC1 and KCC2. Signaling via the nicotinic receptor, a7nAChR, is a key driver of the GABA excitatory/inhibitory [E/I] shift necessary for normative neurodevelopment. Dysfunctional maturation of GABAergic neurotransmission and E/I balance in the brain is implicated in the pathogenesis of several neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASDs). Recently, our studies have identified a functional polymorphism in the Neuregulin 1 gene promoter, rs6994992, which is associated with elevated brain transcription of a novel NRG1 isoform, (NRG1-IV) and more critically lower levels of α7nAChR in the human brain. Signaling via the α7nAChR is a critical driver of the GABA excitatory/inhibitory (E/I) shift, mediated via the chloride transporters, NKCC1 and KCC2 and is also a known genetic risk factor for several NDDs, especially ASD, in the form of 15q13.3 microdeletion syndrome. In rodents, α7nAChR knockdown prevents the switch, resulting in aberrant maturation of GABAergic hyperpolarization and NRG1 is a key regulator of α7nAChRs; the specific role of NRG1-IV is unknown. In human studies, rs6994992 is associated with human cognition, sensory processing and anxiety behaviors, and data from our lab suggest attenuated sensory processing in babies carrying the T allele, and an interaction with maternal gestational dietary choline supplementation. Choline is a α7nAChR agonist, and a novel prenatal nutrient supplementation strategy shown to improve childhood behaviors and early brain development. In summary, the objective of this multidisciplinary proposal is the developmental characterization of a novel biological pathway linking NRG1, α7nAChR and NKCC1/KCC2 with regulation of E/I balance maturation, using a novel transgenic mouse (NRG1- IVtgNSE-tTA) genetically modified to express human NRG1-IV in brain and cutting-edge experimental approaches. We will test two main hypotheses.1). NRG1-IV overexpression contributes to atypical maturation of neocortical GABAergic signaling and E/I cortical balance, mediated via reduced α7nAChR and developmental expression of the chloride co-transporters NKCC1 and KCC2 and 2). Prenatal stimulation of α7nAChR, via dietary choline supplementation, will correct development of the switch, improve adult E/I cortical imbalance and neurobehavioral outcomes relevant to several NDDs, mechanistically via a7nAChR. This research will improve our knowledge of basic mechanisms of typical and atypical development related to a key signaling pathways involved in several NDDs, especially ASD, and identify new treatment/intervention approaches for people with developmental disabilities.