High-frequency head impact causes chronic synaptic adaptation and long-term cognitive impairment in mice

Stephanie S. Sloley, Bevan S. Main, Charisse N. Winston, Alex C. Harvey, Alice Kaganovich, Holly T. Korthas, Adam P. Caccavano, David N. Zapple, Jian-young Wu, John G. Partridge, Mark R. Cookson, Stefano Vicini and Mark P. Burns ()
Additional contact information
Stephanie S. Sloley: Georgetown University Medical Center
Bevan S. Main: Georgetown University Medical Center
Charisse N. Winston: Georgetown University Medical Center
Alex C. Harvey: Georgetown University Medical Center
Alice Kaganovich: National Institute of Aging
Holly T. Korthas: Georgetown University Medical Center
Adam P. Caccavano: Georgetown University Medical Center
David N. Zapple: Georgetown University Medical Center
Jian-young Wu: Georgetown University Medical Center
John G. Partridge: Georgetown University Medical Center
Mark R. Cookson: National Institute of Aging
Stefano Vicini: Georgetown University Medical Center
Mark P. Burns: Georgetown University Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract Repeated head impact exposure can cause memory and behavioral impairments. Here, we report that exposure to non-damaging, but high frequency, head impacts can alter brain function in mice through synaptic adaptation. High frequency head impact mice develop chronic cognitive impairments in the absence of traditional brain trauma pathology, and transcriptomic profiling of mouse and human chronic traumatic encephalopathy brain reveal that synapses are strongly affected by head impact. Electrophysiological analysis shows that high frequency head impacts cause chronic modification of the AMPA/NMDA ratio in neurons that underlie the changes to cognition. To demonstrate that synaptic adaptation is caused by head impact-induced glutamate release, we pretreated mice with memantine prior to head impact. Memantine prevents the development of the key transcriptomic and electrophysiological signatures of high frequency head impact, and averts cognitive dysfunction. These data reveal synapses as a target of high frequency head impact in human and mouse brain, and that this physiological adaptation in response to head impact is sufficient to induce chronic cognitive impairment in mice.

Date: 2021
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DOI: 10.1038/s41467-021-22744-6

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