Transcriptomic and epigenetic profiles of basal ganglia-cortex networks in developmental epileptic encephalopathies

发育性癫痫脑病中基底节-皮质网络的转录组学和表观遗传学特征

• 批准号: 497785435
• 负责人: Professor Dr. Dirk Isbrandt
• 金额: --
• 依托单位: Physiologie II: Sinnes- und Neurophysiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/497785435?language=en
• 关键词: Transcriptomic; epigenetic; profiles; basal; ganglia

Neurodevelopmental disorders share many clinical comorbidities such as impaired motor skills and behavioral deficits, suggesting overlapping pathophysiological mechanisms and common disease pathways. The developmental maturation of neuronal circuits through the formation and refining of synaptic connections is paralleled by dynamic changes in intrinsic excitability. Immature cortical networks show self-organization driven by intrinsically generated activity. For the proper maturation of functional architecture, however, sensory stimulation is required. Impaired cortical processing of sensory input, caused, for example, by shifts in the excitatory-inhibitory balance, affects critical developmental windows and triggers maladaptive neuroplasticity. We propose that, similar to these critical periods in sensory development, vulnerable periods may also exist for the development of higher motor functions. Consequently, prophylactic treatment targeted to these vulnerable periods of motor development may be crucial for disease prevention, as we previously showed in a proof-of-concept study in mouse Kv7 encephalopathy. The development and maturation of the basal ganglia, an essential brain network for motor control, has only recently become a research focus in the context of e.g. Attention-Deficit-Hyperactivity Disorder and Autism Spectrum Disease. Here, he roles of cortical excitability and dopamine function are investigated during postnatal development when goal-oriented motor programs begin to manifest and activity-dependent synapse formation occurs. Importantly, cortico-striatal connectivity and its neuromodulation are sensitive to acute and chronic pertubations in the balance of activity in direct and indirect striatal pathways, which in turn appear to control the excitatory innervation of the striatum. However, the developmental interplay of dopamine and cortico-striatal network maturation is not well understood. We hypothesize that disturbed neural network development underlies dysfunction of motor behavior in channelopathies. We postulate that mutations in ion channel genes, through changes in intrinsic neuronal properties altering cortical neuronal and network excitability, also affects the structural and functional maturation of developing subcortical networks such as the basal ganglia. This process then causes persistent functional and structural changes underlying life-long motor dysfunction. Here, we focus on two ion channel families, Kv7/M and HCN/h channels, whose dysfunction causes pronounced behavioral deficits in transgenic mouse models and aim at identifying the effects of perturbed development on the epigenomic and transcriptomic profiles of projection-specific dopamine midbrain neurons as key players of the basal ganglia. Given that neurodevelopmental perturbations result in clinically relevant changes in the adult DA system – also in a projection-selective fashion – we believe that our complementary approach is timely and relevant.

神经发育障碍具有许多临床合并症，例如运动技能受损和行为定义，表明病理生理机制重叠和常见疾病途径。神经元电路通过形成和突触连接的完善的发展成熟与内在令人兴奋的动态变化相似。未成熟的皮质网络显示出由本质上产生的活性驱动的自组织。但是，对于功能架构的正确成熟，需要感觉刺激。感官输入的皮质处理受损，例如，兴奋性平衡的变化会影响关键的发育窗口，并触发不良适应性神经质量。我们建议，与感觉发展中的这些关键时期类似，较高运动功能的发展也可能存在脆弱的时期。因此，正如我们先前在小鼠KV7脑病中的概念证明研究中所示，针对这些脆弱运动期的预防治疗对于预防疾病可能至关重要。基本神经节的发展和成熟是一种用于运动控制的基本大脑网络，直到最近才成为例如注意力缺陷型疾病和自闭症谱系疾病。在这里，当以目标导向的运动程序开始显现并依赖于活动依赖性突触形成时，在产后发育过程中研究了皮质刺激性和多巴胺功能的作用。重要的是，皮质 - 纹状体连通性及其神经调节对直接和间接纹状体途径的活性平衡中的急性和慢性渗透敏感，这反过来又控制了纹状体的兴奋神经。但是，多巴胺和皮质 - 纹状体网络成熟的发展相互作用尚不清楚。我们假设影响的神经元网络发展是通道路径中运动行为功能障碍的基础。我们假设离子通道基因中的突变通过改变皮质神经元和网络兴奋性的内在神经元特性的变化也影响了发展中皮层网络（如低音神经节）的结构和功能成熟。然后，此过程会导致终身运动功能障碍的持续功能和结构变化。在这里，我们专注于两个离子频道家族KV7/M和HCN/H频道，它们的功能障碍导致明显的行为定义了转基因鼠标模型，旨在确定扰动发育对基本群体占据键入占据键入的投射特异性多巴胺神经元的表观构想和转录组的影响。鉴于神经发育扰动会导致成人DA系统的临床相关变化 - 也以一种投射选择性的方式变化 - 我们认为我们的完整方法是及时且相关的。