Abstract
Traumatic brain injury (TBI) is one of the major causes of death and disability. Multiple animal models have been developed to explore therapeutic targets for TBI. However, heterogeneity of pathophysiology obstructs discovery of therapeutic targets. To facilitate understanding of TBI pathophysiology, each element of neuronal and glial responses should be studied separately. We focused on synapse remodeling which plays an important role in recovery from TBI and developed a new method, afferent elimination, for analyzing synapse remodeling after selective damage to presynaptic axons by mechanical transection in culture of mouse hippocampal neurons. Afferent elimination can induce various events related to synapse remodeling and we could determine their temporal orders and find relationships between them. Specifically, loss of presynaptic sites preceded loss of postsynaptic sites and spines. Some of the postsynaptic sites initially located inside spines showed translocation toward dendritic shafts. These translocation events started after the loss of contacting presynaptic sites. Also, these events could be blocked or delayed by NMDA receptor inhibition. Taken together, these findings suggest that postsynaptic changes occur in afferent elimination are NMDA dependent and imply that these NMDA-dependent events underlie synaptic remodeling of TBI.
Significance Statement Traumatic brain injury (TBI) is one of the major causes of death and disability. However, heterogeneity of TBI pathophysiology obstructs discovery of therapeutic targets. To solve this, each element of neuronal and glial responses should be studied separately. We focused on synapse remodeling which plays an important role in recovery from TBI and developed a new method, afferent elimination. Afferent elimination can induce various events related to synapse remodeling and we could determine their temporal orders and find relationships between them. Also, these events could be blocked by NMDA receptor inhibition. Taken together, these findings suggest that postsynaptic changes after afferent elimination are NMDA receptor-dependent and imply that NMDA receptor-related signaling underlies synaptic remodeling in TBI.
Footnotes
The authors report no conflict of interest.
This study was supported by Grants-in-Aid for Scientific Research (17H01387 and 18H04727 to SO), Core Research for Evolutional Science and Technology from the Japan Science and Technology Agency (JPMJCR14W2 to SO), the Project for Elucidating and Controlling Mechanisms of Aging and Longevity from the Japan Agency for Medical Research and Development (17gm5010003 to SO), and the UTokyo Center for Integrative Science of Human Behavior (CiSHuB).
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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