Impact of astrocytic networks in the adult dentate gyrus on neuronal network function, plasticity and behavior

• Applicants: Professor Dr. Christian Alzheimer; Professorin Dr. Ruth Beckervordersandforth; Professor Christian P. Müller, Ph.D.; Dr. Fang Zheng
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 571482213

Going far beyond the traditional view that astrocytes primarily serve to supply and stabilize CNS neurons, they are now seen as important regulators of neuronal circuits and the behaviors they control. To fulfill these tasks, astrocytes occur in a surprisingly large variety of phenotypes that are tailored to the specific requirements of the respective brain region. Our recently published findings on the layer-specific expression of astrocytic networks in the dentate gyrus (GD) of the hippocampus strongly support this modern concept. With our project proposal, we now want to investigate the functional significance of the strongly coupled astrocytic syncytia in the molecular and granule cell layer of the GD for its inherent neuronal activity and plasticity. We want to clarify to what extent the characteristic neurophysiological properties of adult granule cells depend on their embedding in adequately coupled astrocytic syncytia. To this end, we will disable gap junction-mediated coupling of astrocytes using a conditional and layer-specific double knockout (KO) of connexins 30 and 43 in adult mice and measure the corresponding effects on the neurophysiological signatures of the granule cells. In parallel, the effects of uncoupling on morphology, number and reactivity of the astrocytes themselves will be investigated. In addition, we will investigate the effects of the double KO on adult neurogenesis in the GD, which represents a unique and clinically important plasticity mechanism in addition to the widespread synaptic plasticity phenomena such as LTP and LTD. We will investigate the behavioral consequences of the temporary loss of the extensive astrocyte networks in the GD using established test batteries that measure cognitive performance in learning and memory on the one hand and identify depression- and anxiety-like behavioral patterns on the other. Interestingly, Cx43 can also enable a direct exchange of substances between astrocytes and the extracellular space via the formation of isolated hemichannels (HCs) in the cell membrane. For a long time, the occurrence of such Cx43HCs was considered a sign of a pathologically altered state. However, Cx43HC activity is now also associated with physiological processes such as synaptic plasticity. Using selective blockade of Cx43HC activity in the hippocampal slice as well as in the GD of living animals, we aim to elucidate the physiological significance of this additional function of Cx43 at the cellular, network and behavioral level.

• DFG Programme: Research Grants