Time-dependent homeostatic mechanisms underlie brain-derived neurotrophic factor action on neural circuitry

• Published in: Communications biology 2023-12, Vol.6 (1), p.1278-1278, Article 1278
• Main Authors: O’Neill, Kate M., Anderson, Erin D., Mukherjee, Shoutik, Gandu, Srinivasa, McEwan, Sara A., Omelchenko, Anton, Rodriguez, Ana R., Losert, Wolfgang, Meaney, David F., Babadi, Behtash, Firestein, Bonnie L.
• Format: Article
• Language: English
• Subjects: 13/1; 14/1; 14/19; 631/378/116/1925; 631/378/3920; 631/378/87; 9/30; Biomedical and Life Sciences; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Brain-Derived Neurotrophic Factor - pharmacology; Cells, Cultured; Central nervous system; Clinical trials; Computational neuroscience; Excitotoxicity; Functional morphology; Glutamic Acid - metabolism; Hippocampus; Homeostasis; Homeostatic plasticity; Life Sciences; Neural networks; Neuroimaging; Neurons - physiology; Neuroplasticity; Simulation; Synapses - metabolism
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-023-05638-9

Plasticity and homeostatic mechanisms allow neural networks to maintain proper function while responding to physiological challenges. Despite previous work investigating morphological and synaptic effects of brain-derived neurotrophic factor (BDNF), the most prevalent growth factor in the central nervous system, how exposure to BDNF manifests at the network level remains unknown. Here we report that BDNF treatment affects rodent hippocampal network dynamics during development and recovery from glutamate-induced excitotoxicity in culture. Importantly, these effects are not obvious when traditional activity metrics are used, so we delve more deeply into network organization, functional analyses, and in silico simulations. We demonstrate that BDNF partially restores homeostasis by promoting recovery of weak and medium connections after injury. Imaging and computational analyses suggest these effects are caused by changes to inhibitory neurons and connections. From our in silico simulations, we find that BDNF remodels the network by indirectly strengthening weak excitatory synapses after injury. Ultimately, our findings may explain the difficulties encountered in preclinical and clinical trials with BDNF and also offer information for future trials to consider. A study uses MEA analysis, computation, and simulations to demonstrate how BDNF treatment after excitotoxic injury remodels hippocampal networks by promoting inhibitory neuron survival while indirectly strengthening weak excitatory synapses.