Regulation of the time-sensitive period in neuronal circuit development by NTRK2/TrkB signalling.

NTRK2/TrkB 信号传导调节神经元回路发育的时间敏感期。

• 批准号: MR/W005166/1
• 负责人: Liliana Minichiello
• 金额: $ 69.88万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW005166%2F1
• 关键词: Regulation; time; sensitive; period; neuronal

Maturation of the mammalian brain occurs postnatally and is based on specific developmental programmes of gene transcription. Early in postnatal development, activity shapes neuronal circuits during specific time frames. Neuronal dysfunction at these critical times leads to neurodevelopmental disorders, such as intellectual disabilities, autism and schizophrenia, affecting adult brain functions. Several studies have reported that the neurotransmitter GABA drives early developmental events such as forming and refining neuronal circuits through its early excitatory effects on neural precursors and immature neurons at critical times. This effect occurs in diverse brain regions, including the hippocampus, a structure involved in higher brain functions, such as learning and memory, and spatial coding. Altering this early excitatory effect of GABA gives rise to an array of neurodevelopmental disorders. We have recently established the genetic importance of the neurotrophin receptor TrkB shaping hippocampal neuronal circuitry at a critical period by controlling the GABAergic system development. Namely, altering TrkB signalling in specific hippocampal cells at an early stage of development induces neuronal defects similar to those found in many neurodevelopmental disorders and leads to permanent cognitive dysfunction in adulthood. However, we still lack a deeper understanding of the molecular mechanisms shaping development during critical periods of plasticity. Here, we propose integrated approaches to understand how TrkB signalling-dependent transcription at critical times promotes the refinement and plasticity of neural circuits for cognitive function and what could go wrong in disease. To achieve this, we will combine precise genetics with cutting-edge sequencing techniques, including a computational integrated analysis of single-cell transcriptome and epigenome that will help to select top candidate genes for functional validation analysis. Together, this will provide new insights and new potential genetic factors that regulate time-sensitive periods during the development of hippocampal circuits. These studies are vital for understanding the molecular mechanisms responsible for the onset of neurodevelopmental disorders, both in terms of basic mechanisms and clinical application. Thus, this project is timely and innovative in the field of neurodevelopmental disorders.

哺乳动物大脑的成熟发生在出生后，并且基于基因转录的特定发育程序。在出生后发育的早期，活动在特定的时间范围内塑造神经元回路。在这些关键时刻的神经元功能障碍会导致神经发育障碍，如智力残疾、自闭症和精神分裂症，影响成年人的大脑功能。几项研究报告说，神经递质GABA驱动早期发育事件，如形成和完善神经元回路，通过其早期兴奋作用的神经前体和未成熟的神经元在关键时刻。这种效应发生在不同的大脑区域，包括海马体，海马体是一种涉及高级大脑功能的结构，如学习和记忆以及空间编码。改变GABA的这种早期兴奋作用会引起一系列神经发育障碍。我们最近建立了神经营养因子受体TrkB的遗传重要性，在关键时期通过控制GABA能系统的发展塑造海马神经元回路。也就是说，在发育的早期阶段改变特定海马细胞中的TrkB信号传导诱导类似于在许多神经发育障碍中发现的神经元缺陷，并导致成年后的永久性认知功能障碍。然而，我们仍然缺乏对可塑性关键时期形成发育的分子机制的更深入理解。在这里，我们提出了综合的方法来了解TrkB信号依赖性转录在关键时刻如何促进认知功能神经回路的完善和可塑性，以及疾病中可能出现的问题。为了实现这一目标，我们将把联合收割机精确遗传学与尖端测序技术相结合，包括对单细胞转录组和表观基因组的计算综合分析，这将有助于选择最佳候选基因进行功能验证分析。总之，这将提供新的见解和新的潜在遗传因素，调节海马电路发育过程中的时间敏感期。这些研究对于理解神经发育障碍发病的分子机制至关重要，无论是在基本机制还是临床应用方面。因此，该项目在神经发育障碍领域是及时和创新的。

项目成果

NKCC1 Deficiency in Forming Hippocampal Circuits Triggers Neurodevelopmental Disorder: Role of BDNF-TrkB Signalling.

• DOI: 10.3390/brainsci12040502
• 发表时间: 2022-04-15
• 期刊: BRAIN SCIENCES
• 影响因子: 3.3
• 作者: Szymanski, Jacek;Minichiello, Liliana
• 通讯作者: Minichiello, Liliana