Molecular and network mechanisms-derived targeted interventions in neonatal genetic epilepsies

新生儿遗传性癫痫的分子和网络机制衍生的靶向干预

• 批准号: 394774896
• 负责人: Professor Dr. Albert Becker
• 金额: --
• 依托单位: Institut für Neuropathologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/394774896?language=en
• 关键词: Molecular; network; mechanisms; derived; targeted

During early life, the brain is particularly prone to both internal perturbations and external insults, which can lead to lifelong cognitive deficits and epilepsy. Brain and neuronal network development depend on a complex sequence of events, which include neurogenesis, migration, differentiation, synaptogenesis, and synaptic pruning. Perturbations to any of these processes, for example associated with ion channel gene mutations, can underlie neurodevelopmental disorders such as epilepsy, which is characterized by hyperexcitable neuronal networks and often manifests in the neonatal period or early infancy. The therapeutic options available, especially for early infantile epileptic encephalopathies (EE), are very limited, and prophylactic therapies for patients at an increased risk of developing such epilepsies do not exist yet. However, the plasticity of the developing brain suggests a great therapeutic potential. We propose that, similar to critical periods in sensory development, which depend on the precise temporal maturation of GABAergic signaling and a proper balance of excitation and inhibition, vulnerable periods may also exist in the pathogenesis of EEs. In a proof-of-concept study1, we recently demonstrated in a genetic mouse model of KV7 encephalopathy that prophylactic treatment aimed at a vulnerable period prevented the development of the disease. We will now investigate in a mouse model of EE caused by the missense mutation (p.Ala263Val) in the Scn2a gene, which leads to a gain of function in the voltage-gated Na+ channel NaV1.22, whether a vulnerable period can also be identified and a prophylactic treatment be developed. In the framework of the RU, this model will be jointly characterized with respect to the temporal dynamics of in vivo hippocampal and cortical network activity during brain maturation, the consequences for neuronal structure and function, region- and cell population-specific transcriptomic changes during epileptogenesis, the presence of a vulnerable time window, and the prophylactic or disease-modifying efficacy of timed treatments and manipulations.

在生命早期，大脑特别容易受到内部干扰和外部损伤，这可能导致终身的认知缺陷和癫痫。脑和神经元网络的发育依赖于一系列复杂的事件，包括神经发生、迁移、分化、突触发生和突触修剪。对这些过程中的任何一个的扰动，例如与离子通道基因突变相关的扰动，可以成为神经发育障碍如癫痫的基础，癫痫的特征在于过度兴奋的神经元网络，并且通常在新生儿期或婴儿早期显现。可用的治疗选择，特别是对于早期婴儿癫痫性脑病（EE），是非常有限的，并在发展这样的癫痫风险增加的患者的预防性治疗还不存在。然而，发育中的大脑的可塑性表明了巨大的治疗潜力。我们建议，类似的感觉发育的关键时期，这取决于精确的时间成熟的GABA能信号和适当的平衡的兴奋和抑制，脆弱的时期也可能存在于EEs的发病机制。在一项概念验证研究1中，我们最近在KV7脑病的遗传小鼠模型中证明，针对易感期的预防性治疗可以预防疾病的发展。我们现在将研究由Scn2a基因中的错义突变（p.Ala263Val）引起的EE小鼠模型，该突变导致电压门控Na+通道NaV1.22的功能获得，是否也可以识别脆弱期并开发预防性治疗。在RU的框架内，该模型将联合表征脑成熟过程中体内海马和皮质网络活动的时间动态，神经元结构和功能的后果，癫痫发生过程中区域和细胞群体特异性转录组学变化，脆弱时间窗的存在，以及定时治疗和操作的预防或疾病修饰功效。