2025/07/24 by Steffi Schumacher, Sara Neyt, Christian Vanhove +4 · 1 voice
Biochemistry, Genetics and Molecular Biology · Neuroscience · #Barrier Structure and Function Studies #Connexins and lens biology #Neuroscience and Neuropharmacology Research
paper · doi:10.1002/glia.70063
openalex publication_date 2025/07/24 · openalex created_date 2025/07/25 · openalex updated_date 2026/07/22
ABSTRACT Radiation therapy is widely used for treating brain tumors but also comes with off‐target effects, including vascular blood–brain barrier (BBB) leakage occurring as an early event 24 h postirradiation. Here we investigated brain X‐irradiation (20 Gy) effects on the astrocyte‐neuronal axis starting from BBB endothelium and ending at synapses. Making use of immune‐characterization of brain slices isolated 24 h after irradiation of rodents, we found significantly decreased neuronal expression of GLUT3 glucose transporters and MCT2 monocarboxylate transporters in M1/S1 cortical areas, with no changes in astrocytic GLUT1 transporters. Pre‐irradiation animal treatment with the Cx43 hemichannel blocker TATGap19 targeting astrocytes completely prevented these neuronal alterations. Brain uptake of 18 F‐deoxy‐glucose was decreased in the pre‐ and infra‐limbic cortex 24 h postirradiation, not in other cortical areas, and was prevented by TATGap19 treatment. Electro‐encephalographic recordings showed decreased power in delta, theta, beta, and gamma bands, most clearly in S1 cortex 24 h postirradiation. ProBDNF, a precursor of brain‐derived neurotrophic factor associated with negative neural effects, was significantly elevated 24 h postirradiation and accompanied by strong activation of its vesicular transport in astrocytes. In particular, proBDNF uptake in astrocytic endfeet at capillary endothelial cells and its VAMP3‐associated release at astrocytic extensions to tripartite synapses were both strongly increased and prevented by animal pretreatment with TATGap19. The present data show that astrocytes are a major target for radiotherapeutic intervention whereby Gap19 inhibition of the Cx43 hemichannel membrane leakage pathway prevents radiation‐induced alterations in brain glucose handling and activation of vesicular proBDNF transport to tripartite synapses that disturb neural functioning.