Panglial coupling and the metabolic support of axons and synapses

• Applicants: Professor Dr. Christian Steinhäuser; Privatdozentin Dr. Susanne A. Wolf, since 1/2023
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2013 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 235153551

• Final Report Year: 2024

Final Report Abstract

The brain is dominated by two cell populations, neurons and glial cells. Neurons mediate electrical activity in the brain. Glial cells are not only supporting elements but also interact with neurons and influence the transmission of information in the central nervous system (CNS). Here we focused on macroglial cells, namely oligodendrocytes, astrocytes and the so-called NG2 glial cells, and studied properties and consequences of their interactions via gap junctions, which serve as communication and transport channels between these cells. By means of gap junctions, glial cells form networks which serve the metabolic support of neurons and the modulation of neuronal activity. Yet, the majority of such neuron-glial interactions were analyzed in the grey matter. In the current project, we have developed a novel preparation allowing also studying gap junctional communication with patch-clamp and tracer-filling in white matter, in optic nerve tissue slices. This structure is actually not a classical nerve, but part of the CNS and thus contains the typical macroglia of the CNS. Using acute preparations of the optic nerve from reporter mouse lines, we were able to characterize the essential macroglia elements electrophysiologically for the first time, and show with tracer filling and subsequent immunostaining that these cells are coupled, however, to a much lower extend than in grey matter such as in cortex and hippocampus. We also found that the glial cells express functional transmitter receptors, namely glutamate and GABAA receptors. In a further approach, we investigated the impact of macroglial coupling on information processing in the thalamus. First, using field potential recordings and intracellular application of energy metabolites, we were able to show that panglial gap junction coupling between oligodendrocytes and astrocytes in the ventrobasal thalamus is of crucial importance for the maintenance of synaptic activity in this brain region. We then investigated whether and by which mechanisms neuronal activity affects the efficiency of panglial coupling in the thalamus. In acute brain slices, inhibition of action potentials led to a reduction in coupling efficiency. Systematic analyses of mouse lines with deletions of individual connexin isoforms, the proteins that form the gap junctions, has shown that connexins 32 and 47, which are expressed by oligodendrocytes, are the target of this modulation. Finally, we were able to show that in a critical time window after sensory deprivation, by unilateral removal of the whiskers, the panglial coupling networks are also modulated in vivo. Thus, our results show that in the thalamus, panglial coupling is essential for the energetic supply of neurons and, conversely, that neuronal activity regulates the efficiency of glial energy transfer. Overall, our joint project has thus demonstrated that and how properties and functions of glial networks differ across brain regions.

Publications

• Astrocytes and oligodendrocytes in the thalamus jointly maintain synaptic activity by supplying metabolites. Cell Reports, 34(3), 108642.
  Philippot, Camille; Griemsmann, Stephanie; Jabs, Ronald; Seifert, Gerald; Kettenmann, Helmut & Steinhäuser, Christian
  
• Cx43 carboxyl terminal domain determines AQP4 and Cx30 endfoot organization and blood brain barrier permeability. Scientific Reports, 11(1).
  Cibelli, Antonio; Stout, Randy; Timmermann, Aline; de Menezes, Laura; Guo, Peng; Maass, Karen; Seifert, Gerald; Steinhäuser, Christian; Spray, David C. & Scemes, Eliana
  
• Targeting gliovascular connexins prevents inflammatory blood-brain barrier leakage and astrogliosis. JCI Insight, 7(16).
  De Bock, Marijke; De Smet, Maarten; Verwaerde, Stijn; Tahiri, Hanane; Schumacher, Steffi; Van Haver, Valérie; Witschas, Katja; Steinhäuser, Christian; Rouach, Nathalie; Vandenbroucke, Roosmarijn E. & Leybaert, Luc
  
• Role of Impaired Astrocyte Gap Junction Coupling in Epileptogenesis. Cells, 12(12), 1669.
  Bedner, Peter & Steinhäuser, Christian
  
• Activity dependent modulation of glial gap junction coupling in the thalamus. iScience, 27(10), 111043.
  Baum, Paula; Beinhauer, Anna; Zirwes, Lara; Loenneker, Linda; Jabs, Ronald; Narayanan, Rajeevan T.; Oberlaender, Marcel; Seifert, Gerald; Kettenmann, Helmut & Steinhäuser, Christian
  
• Membrane properties and coupling of macroglia in the optic nerve. Current Research in Neurobiology, 7(2024), 100137.
  Kompier, Nine; Semtner, Marcus; Walter, Sophie; Kakabadze, Natali; Steinhäuser, Christian; Nolte, Christiane & Kettenmann, Helmut
  
• The IgCAM BT-IgSF (IgSF11) Is Essential for Connexin43-Mediated Astrocyte–Astrocyte Coupling in Mice. eneuro, 11(3), ENEURO.0283-23.2024.
  Pelz, Laura; Dossou, Laura; Kompier, Nine; Jüttner, René; Siemonsmeier, Gabrielle; Meyer, Niklas; Lowenstein, Elijah D.; Lahmann, Ines; Kettenmann, Helmut; Birchmeier, Carmen & Rathjen, Fritz G.