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

神经发育障碍具有许多临床共病，如运动技能受损和行为缺陷，提示重叠的病理生理机制和常见的疾病途径。神经元回路通过突触连接的形成和完善而发育成熟，与内在兴奋性的动态变化是平行的。不成熟的大脑皮层网络显示出由内在活动驱动的自组织。然而，为了功能结构的适当成熟，感官刺激是必需的。感觉输入的皮层处理受损，例如，由兴奋-抑制平衡的变化引起，影响关键的发育窗口，并触发适应不良的神经可塑性。我们认为，与感觉发育的这些关键期类似，高级运动功能的发展也可能存在脆弱时期。因此，针对这些运动发育的脆弱时期的预防性治疗可能是疾病预防的关键，正如我们之前在小鼠KV7脑病的概念验证研究中所表明的那样。基底神经节的发育和成熟是运动控制的基本大脑网络，直到最近才成为注意缺陷多动障碍和自闭症谱系疾病背景下的研究重点。在这里，他研究了皮质兴奋性和多巴胺功能在出生后发育过程中的作用，当时以目标为导向的运动程序开始显现，并出现活动依赖的突触形成。重要的是，皮质-纹状体的连接及其神经调节对直接和间接纹状体通路的活动平衡中的急性和慢性扰动很敏感，这反过来似乎控制着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还不是很清楚。我们假设神经网络发育障碍是沟道病患者运动行为功能障碍的基础。我们推测，离子通道基因的突变，通过改变皮质神经元和网络的兴奋性，改变固有的神经元属性，也影响发育中的皮质下网络(如基底节)的结构和功能成熟。这个过程随后会导致持续的功能和结构变化，这是终身运动功能障碍的基础。在这里，我们关注两个离子通道家族，KV7/M和HCN/h通道，它们的功能障碍导致转基因小鼠明显的行为缺陷，目的是确定发育受扰对作为基底节关键角色的投射特异性多巴胺中脑神经元的表观基因组和转录图谱的影响。鉴于神经发育紊乱导致成人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。

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.