High-frequency Head Impact Causes Chronic Synaptic Adaptation and Long-term Cognitive Impairment in Mice

Overview

Journal Nat Commun

Specialty Biology

Date 2021 May 11

PMID 33972519

Citations 27

Authors

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

Mark P Burns

Affiliations

Soon will be listed here.

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.

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References

Hof P, Bouras C, Buee L, Delacourte A, Perl D, Morrison J . Differential distribution of neurofibrillary tangles in the cerebral cortex of dementia pugilistica and Alzheimer's disease cases. Acta Neuropathol. 1992; 85(1):23-30. DOI: 10.1007/BF00304630. View

Hay J, Johnson V, Smith D, Stewart W . Chronic Traumatic Encephalopathy: The Neuropathological Legacy of Traumatic Brain Injury. Annu Rev Pathol. 2016; 11:21-45. PMC: 5367053. DOI: 10.1146/annurev-pathol-012615-044116. View

McKee A, Cantu R, Nowinski C, Hedley-Whyte E, Gavett B, Budson A . Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol. 2009; 68(7):709-35. PMC: 2945234. DOI: 10.1097/NEN.0b013e3181a9d503. View

Talavage T, Nauman E, Breedlove E, Yoruk U, Dye A, Morigaki K . Functionally-detected cognitive impairment in high school football players without clinically-diagnosed concussion. J Neurotrauma. 2010; 31(4):327-38. PMC: 3922228. DOI: 10.1089/neu.2010.1512. View

Ren Z, Iliff J, Yang L, Yang J, Chen X, Chen M . 'Hit & Run' model of closed-skull traumatic brain injury (TBI) reveals complex patterns of post-traumatic AQP4 dysregulation. J Cereb Blood Flow Metab. 2013; 33(6):834-45. PMC: 3677112. DOI: 10.1038/jcbfm.2013.30. View

Mouzon B, Bachmeier C, Ferro A, Ojo J, Crynen G, Acker C . Chronic neuropathological and neurobehavioral changes in a repetitive mild traumatic brain injury model. Ann Neurol. 2013; 75(2):241-54. DOI: 10.1002/ana.24064. View

Creed J, DiLeonardi A, Fox D, Tessler A, Raghupathi R . Concussive brain trauma in the mouse results in acute cognitive deficits and sustained impairment of axonal function. J Neurotrauma. 2011; 28(4):547-63. PMC: 3070143. DOI: 10.1089/neu.2010.1729. View

Kane M, Angoa-Perez M, Briggs D, Viano D, Kreipke C, Kuhn D . A mouse model of human repetitive mild traumatic brain injury. J Neurosci Methods. 2011; 203(1):41-9. PMC: 3221913. DOI: 10.1016/j.jneumeth.2011.09.003. View

Laurer H, Bareyre F, Lee V, Trojanowski J, Longhi L, Hoover R . Mild head injury increasing the brain's vulnerability to a second concussive impact. J Neurosurg. 2001; 95(5):859-70. DOI: 10.3171/jns.2001.95.5.0859. View

10.

Prins M, Hales A, Reger M, Giza C, Hovda D . Repeat traumatic brain injury in the juvenile rat is associated with increased axonal injury and cognitive impairments. Dev Neurosci. 2010; 32(5-6):510-8. PMC: 3215244. DOI: 10.1159/000316800. View

11.

Aungst S, Kabadi S, Thompson S, Stoica B, Faden A . Repeated mild traumatic brain injury causes chronic neuroinflammation, changes in hippocampal synaptic plasticity, and associated cognitive deficits. J Cereb Blood Flow Metab. 2014; 34(7):1223-32. PMC: 4083389. DOI: 10.1038/jcbfm.2014.75. View

12.

Petraglia A, Plog B, Dayawansa S, Chen M, Dashnaw M, Czerniecka K . The spectrum of neurobehavioral sequelae after repetitive mild traumatic brain injury: a novel mouse model of chronic traumatic encephalopathy. J Neurotrauma. 2014; 31(13):1211-24. PMC: 4082360. DOI: 10.1089/neu.2013.3255. View

13.

Mouzon B, Chaytow H, Crynen G, Bachmeier C, Stewart J, Mullan M . Repetitive mild traumatic brain injury in a mouse model produces learning and memory deficits accompanied by histological changes. J Neurotrauma. 2012; 29(18):2761-73. DOI: 10.1089/neu.2012.2498. View

14.

Winston C, Noel A, Neustadtl A, Parsadanian M, Barton D, Chellappa D . Dendritic Spine Loss and Chronic White Matter Inflammation in a Mouse Model of Highly Repetitive Head Trauma. Am J Pathol. 2016; 186(3):552-67. PMC: 4816714. DOI: 10.1016/j.ajpath.2015.11.006. View

15.

Meehan 3rd W, Zhang J, Mannix R, Whalen M . Increasing recovery time between injuries improves cognitive outcome after repetitive mild concussive brain injuries in mice. Neurosurgery. 2012; 71(4):885-91. PMC: 5815628. DOI: 10.1227/NEU.0b013e318265a439. View

16.

Crisco J, Fiore R, Beckwith J, Chu J, Brolinson P, Duma S . Frequency and location of head impact exposures in individual collegiate football players. J Athl Train. 2010; 45(6):549-59. PMC: 2978006. DOI: 10.4085/1062-6050-45.6.549. View

17.

Lalonde R . The neurobiological basis of spontaneous alternation. Neurosci Biobehav Rev. 2002; 26(1):91-104. DOI: 10.1016/s0149-7634(01)00041-0. View

18.

Koliatsos V, Cernak I, Xu L, Song Y, Savonenko A, Crain B . A mouse model of blast injury to brain: initial pathological, neuropathological, and behavioral characterization. J Neuropathol Exp Neurol. 2011; 70(5):399-416. DOI: 10.1097/NEN.0b013e3182189f06. View

19.

Le Meur K, Galante M, Angulo M, Audinat E . Tonic activation of NMDA receptors by ambient glutamate of non-synaptic origin in the rat hippocampus. J Physiol. 2006; 580(Pt. 2):373-83. PMC: 2075557. DOI: 10.1113/jphysiol.2006.123570. View

20.

Seo J, Lee S, Shin J, Hwang Y, Cho H, Yoo S . Transcriptome analyses of chronic traumatic encephalopathy show alterations in protein phosphatase expression associated with tauopathy. Exp Mol Med. 2017; 49(5):e333. PMC: 5454448. DOI: 10.1038/emm.2017.56. View