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

Author:

O’Neill Kate M.ORCID,Anderson Erin D.ORCID,Mukherjee Shoutik,Gandu SrinivasaORCID,McEwan Sara A.,Omelchenko Anton,Rodriguez Ana R.,Losert WolfgangORCID,Meaney David F.,Babadi Behtash,Firestein Bonnie L.ORCID

Abstract

AbstractPlasticity 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.

Funder

National Science Foundation

New Jersey Commission on Brain Injury Research

Coalition for Brain Injury Research Grant to BLF

U.S. Department of Health & Human Services | National Institutes of Health

U.S. Department of Education

University of Maryland

Paul G. Allen Family Foundation

Publisher

Springer Science and Business Media LLC

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

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