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

神经调节蛋白/Alpha7nAChR 信号传导、GABA 能开关和神经发育风险：妊娠期胆碱补充的机制。

基本信息

批准号：
10711908
负责人：
Amanda Jayne Law
金额：
$ 51.16万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-06-30
项目状态：
未结题

项目摘要

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.

项目摘要在早期大脑发育期间，GABA是由于反向氯化剂而引起的激发剂通过氯化物的转运蛋白基因NKCC1和KCC2介导。 A7NACHR是GABA兴奋性/抑制性[E/I]的关键驱动力，正常偏移。 GABA能神经传递和E/I平衡功能障碍与IS中有关白天发育障碍（NDDS）的发病机理，包括自闭症谱系障碍（ASDS）。最近，我们的研究确定了神经蛋白1启动子中的功能多态性，RS6994992，这与新型NRG1同工型（NRG1-IV）的脑转录升高以及更严格的人脑中的α7NACHR水平较低。通过氯化物转运蛋白介导的NKCC1，兴奋/抑制（E/I）偏移，也是已知的以15q13.3微型综合征形式的几个NDD的遗传因素，啮齿动物的形式。 α7NACHR敲低阻止了转换，导致异常成熟的磨牙化和 NRG1是α7NACHR的关键常规者；与人类认知，感觉处理和焦虑行为以及我们实验室Sugest的数据有关携带Tallelele的婴儿的感官过程减弱，以及与孕妇饮食的相互作用补充胆碱。总结起来改善童年行为和早期大脑的发展。多学科建议是连接NRG1的新生物学途径的发展表征 α7NACHR和NKCC1/KCC2，使用一种新型的转基因小鼠（NRG1-- IVTTGNSE-TTA）经过遗传修饰，以表达大脑和尖端实验中的人NRG1-IV 方法。新皮质GABA能信号传导和E/I皮质平衡，通过降低的α7NACHR和发育介导氯化物共转运蛋白的表达NKCC1和KCC2和2）。补充饮食胆碱，将纠正转换的发展，改善成人E/I皮质不平衡和与几个NDD相关的神经性结局，通过A7NACHR进行机械能力。我们对与关键信号通路有关的典型和非典型开发基本机制的基本机制涉及严重的NDD，尤其是ASD和IND IND促进了与WASS一起窥视的新治疗/干预方法。发育不景气。