Interaction of GABAA-receptor function and network activity in the developing hippocampus

• Applicants: Professor Dr. Knut Holthoff; Professor Dr. Knut Kirmse
• Subject Area: Experimental and Theoretical Network Neuroscience ; Developmental Neurobiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 442107075

The proper development of neuronal circuits is highly activity-dependent. While much has been learned about the contribution of sensory-evoked activity to this refinement, the functions of intrinsically generated activity at early stages of brain development are poorly understood. We here examine the hypothesis that mutual interactions between GABAA receptor (GABAAR)-dependent signaling and early correlated network activity instruct the maturation of synaptic and network properties in the developing hippocampus. We build on previous findings indicating that GABAergic transmission exerts both excitatory and inhibitory functions in the neonatal hippocampus. To dissect the roles of GABAAR-dependent signaling, we will interfere with GABA release from molecularly defined GABAergic cells, in particular somatostatin interneurons, which we could show drive correlated activity through excitation of CA1 pyramidal cells in vitro. Presynaptic manipulations will be complemented by postsynaptic interventions involving conditional transgenic models with an altered driving force of GABAAR-mediated currents. Three-dimensional two-photon Ca2+ imaging in combination with electrophysiology will be applied to analyze the spatiotemporal dynamics of CA1 network activity in vivo. In addition, electrophysiological techniques will be used to reveal how manipulations of early network activity affect the proper maturation of synaptic and extrasynaptic GABAAR function during development.

• DFG Programme: Research Grants