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，如运动技能受损和行为缺陷，提示重叠的病理生理机制和共同的疾病途径。通过突触连接的形成和完善，神经元回路的发育成熟与内在兴奋性的动态变化是并行的。未成熟的皮层网络表现出由内在产生的活动驱动的自组织。然而，对于功能性建筑的适当成熟，感官刺激是必需的。例如，兴奋-抑制平衡的改变会导致感觉输入的皮质加工受损，影响关键的发育窗口期，引发神经可塑性不良。我们认为，与感官发育的这些关键时期类似，高级运动功能的发展也可能存在脆弱期。因此，正如我们之前在小鼠Kv7脑病的概念验证研究中所显示的那样，针对这些运动发育脆弱期的预防性治疗可能对疾病预防至关重要。基底神经节是运动控制的重要大脑网络，其发育和成熟直到最近才成为注意缺陷多动障碍和自闭症谱系疾病等背景下的研究热点。在此，研究人员研究了大脑皮层兴奋性和多巴胺功能在出生后发育过程中的作用，此时目标导向的运动程序开始显现，活动依赖的突触形成发生。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通路活动平衡的急性和慢性波动敏感，而纹状体通路反过来似乎控制纹状体的兴奋性神经支配。然而，多巴胺和皮质纹状体网络成熟的发育相互作用尚不清楚。我们假设神经网络发育紊乱是通道病中运动行为功能障碍的基础。我们假设离子通道基因的突变，通过改变神经元固有特性改变皮层神经元和网络的兴奋性，也影响发育中的皮层下网络（如基底神经节）的结构和功能成熟。这个过程会导致持续的功能和结构变化，从而导致终身运动功能障碍。在这里，我们关注两个离子通道家族，Kv7/M和HCN/h通道，它们的功能障碍在转基因小鼠模型中导致明显的行为缺陷，并旨在确定失调的发育对作为基底神经节关键参与者的突起特异性多巴胺中脑神经元的表观基因组和转录组谱的影响。考虑到神经发育扰动导致成人DA系统的临床相关变化-也是以投射选择性的方式-我们相信我们的补充方法是及时和相关的。