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

哺乳动物大脑的成熟是在出生后发生的，并基于特定的基因转录发育程序。在出生后发育的早期，活动在特定的时间框架内塑造神经元电路。在这些关键时期，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。一些研究报道，神经递质GABA通过在关键时刻对神经前体和未成熟神经元的早期兴奋作用，推动早期发育事件，如形成和完善神经元回路。这种影响发生在不同的大脑区域，包括海马体，海马体是一种参与更高大脑功能的结构，如学习和记忆，以及空间编码。改变GABA的这种早期兴奋效应会导致一系列神经发育障碍。我们最近通过控制GABA能系统的发育，确定了神经营养素受体TrkB在关键时期塑造海马神经元电路的遗传学重要性。也就是说，在发育早期改变特定海马细胞中的TrkB信号会导致神经元缺陷，类似于许多神经发育障碍，并导致成年后永久性的认知功能障碍。然而，我们仍然缺乏对可塑性关键期发育的分子机制的深入了解。在这里，我们提出了综合的方法来理解TrkB信号依赖的转录如何在关键时刻促进认知功能神经回路的精细化和可塑性，以及疾病中可能出现的问题。为了实现这一目标，我们将把精确遗传学与尖端测序技术结合起来，包括对单细胞转录组和表观基因组的计算集成分析，这将有助于选择最佳候选基因进行功能验证分析。总而言之，这将提供新的见解和新的潜在遗传因素，在海马区电路的发育过程中调节时间敏感期。这些研究对于理解神经发育障碍发生的分子机制至关重要，无论是从基本机制还是临床应用都是如此。因此，该项目在神经发育障碍领域具有时效性和创新性。

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.