Role of tangential migration for cortical network maturation

• Applicants: Professor Dr. Knut Holthoff; Professor Dr. Knut Kirmse; Professor Dr. Ralf Stumm
• Subject Area: Developmental Neurobiology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 448069679

GABAergic interneurons are essential inhibitory elements of the cerebrocortical network. They maintain an excitation/ inhibition balance, generate synchronized network activity during development, and are important for cognitive and emotional processing. Defects in the embryonic development of cortical interneurons (cIN) affect functional maturation of the cortex, which may predispose to neurological and psychiatric disorders. Since cIN are generated in the ventral telencephalon, they need to migrate large distances to become distributed throughout the cortex. It is well established that intracortical dispersion of cIN is under an elaborate genetic control causing cIN to migrate tangentially (i.e. parallel to the brain surface) within specific cortical layers. Still, it is largely unknown whether layer-specific tangential migration is necessary to ensure normal cortical function. Here, we plan to investigate how genetic defects that cause cIN to migrate outside their normal routes affect postnatal maturation of the cortical network. We propose a multi-method approach combining the complementary expertises of the Stumm, Kirmse and Holthoff groups. Specifically, we will examine numbers, layer-acquisition, immediate early gene responses, and transcriptomes of defined cortical neuronal types. This is accompanied by analyses of the maturation of the intrinsic membrane properties and synaptic input-output characteristics of cortical neurons as well as assessments of neuronal network dynamics in vivo. Our studies will be performed in well-established mouse models with genetic defects in the Cxcl12/ Cxcr4/ Ackr3 signaling module, which generates the most important chemotactic signal for tangentially migrating cIN. Our work will help to elucidate how genetic control of tangential migration is linked to the generation of a functional cortical network.

• DFG Programme: Research Grants