Functional in vivo restoration of genetically determined epileptic neocortical circuitry.

• Applicant: Dr. Thomas Wuttke
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 444091233

Most neurodevelopmental, neurodegenerative and acquired CNS diseases are characterized by impairment or loss of specific neuron subpopulations resulting in dysfunctional brain circuits. One neuroregenerative approach is to replenish and reform defective circuitry by exogenous neurons. We recently demonstrated that postnatal neocortical connectivity can be reconstituted with point-to-point precision by transplantation of appropriate neuron subtypes (Wuttke et al., Nat Neurosci, 2018). A complementary strategy is to restore circuit dysfunction through modulation of endogenous neurons and networks. Genetic CNS disorders such as developmental epileptic encephalopathy frequently get diagnosed after significant disease progression has already occurred and after symptoms became obvious, raising the question whether there exists a critical time window for therapeutic intervention. We will investigate whether dysfunctional neocortical circuitry can be restored at incrementally more mature stages and beyond the relatively plastic early postnatal phase. Taking advantage of a recently optimized brain slice culture model we will then approach questions of translatability to the human CNS.

• DFG Programme: Research Grants