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

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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.