The Beckervordersandforth Lab is interested in the cellular and molecular mechanisms underlying plasticity of the mammalian brain. While many studies have been focused on neurons, we aim to unravel the role of astrocytes in modulation and regulation of hippocampal plasticity.
Within the brain, the dentate gyrus (DG) of the hippocampus is unique in its connectivity and its plasticity. Due to the persistence of neurogenesis throughout life one can state that DG development basically "never ends". Adult neurogenesis is regarded as a key contributor to the adult’s brain plasticity as it keeps the brain capable of dynamic cellular and molecular remodeling in response to an individual´s interaction with the outside world. From a clinical point of view adult neurogenesis is highly relevant and dysregulation is evolving as a significant contributor to neuropsychiatric symptoms in ageing and neurodegenerative diseases.
For a long time, it has been thought that hippocampal plasticity is predominantly driven by neurons, however, more recent data indicate an active participation of astrocytes. To date it is known that astrocytes contribute to such plasticity in two ways: firstly, by serving as radial glia-like neural stem cells (NSCs) that give rise to new neurons and glial cells, secondly, by serving as niche cells that control the activity of NSCs, and provide structural and functional support to neurons. Besides extensive investigations of the astrocyte-like radial NSCs, the niche astrocyte compartment has been mostly neglected, and considered to be static and homogeneous. In contrast to this, we discovered that the hippocampal niche is (1.) populated by heterogeneous astrocyte subpopulations, and (2.) constantly changing due to life-long generation of new astrocytes.
We are pursuing the novel hypothesis that the continuous neurodevelopment in the form of astrogenesis may be instrumental for hippocampal plasticity under physiological and pathological conditions. With the aim to understand how the astrocytes niche influence hippocampal plasticity, we need to address the following questions:
When and how are astrocytes generated during hippocampal development?
Which mechanisms contribute to the generation and dynamics of the astrocytic niche?
What are the functions of distinct astrocyte subtypes and how do they contribute to the generation and survival of newborn neurons?
How does are hippocampal astrocytes - their diversity, dynamic and function - affected in neurodegenerative and neuropsychiatric disorders?
Understanding on the contribution of astrocytes to hippocampal neurogenesis and plasticity under physiological conditions is an important step towards better understanding of astropathologies and their contributions to brain diseases.
We investigate these important questions through an integrated approach that combines imaging, single cell transcriptomics and functional genetics.
Dentate gyrus astrocytes exhibit layer-specific molecular, morphological and physiological features
Karpf, J., Unichenko, P., Chalmers, N., Beyer, F., Wittmann, M. T., Schneider, J., ... & Beckervordersandforth, R. (2022). Dentate gyrus astrocytes exhibit layer-specific molecular, morphological and physiological features. Nature Neuroscience, 1-13. DOI: 10.1038/s41593-022-01192-5
Neuronal heterogeneity has been established as a pillar of higher central nervous system function, but glial heterogeneity and its implications for neural circuit function are poorly understood. Here we show that the adult mouse dentate gyrus (DG) of the hippocampus is populated by molecularly distinct astrocyte subtypes that are associated with distinct DG layers. Astrocytes localized to different DG compartments also exhibit subtype-specific morphologies. Physiologically, astrocytes in upper DG layers form large syncytia, while those in lower DG compartments form smaller networks. Astrocyte subtypes differentially express glutamate transporters, which is associated with different amplitudes of glutamate transporter-mediated currents. Key molecular and morphological features of astrocyte diversity in the mice DG are conserved in humans. This adds another layer of complexity to our understanding of brain network composition and function, which will be crucial for further studies on astrocytes in health and disease.