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

Mark P Burns,Charisse N Winston,Alex C Harvey,Mark R Cookson,Holly T Korthas,Jian-Young Wu,Adam P Caccavano,John G Partridge,Stefano Vicini,Stephanie S Sloley,Alice Kaganovich,Bevan S Main,David N Zapple

doi:10.1038/s41467-021-22744-6

Mark P Burns, Charisse N Winston + Show 11 more

Open Access

https://doi.org/10.1038/s41467-021-22744-6

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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.

Highlights

Repeated head impact exposure can cause memory and behavioral impairments
Using paired-pulse ratio recordings of evoked excitatory postsynaptic currents (EPSCs) in the presence of 25 μM bicuculline methobromide (BMR), we found no difference between high-frequency head impact (HF-HI) and sham mice, indicating that presynaptic vesicular release is not changed in the HF-HI brain (Fig. 2e)
Upon the addition of 1 μM tetrodotoxin (TTX), we observed a significant increase in the miniature EPSCs inter-event interval in HF-HI mice, which occurred in the absence of changes to mEPSC amplitude (Fig. 2f–h)

Summary

Introduction

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. 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. We report that exposure to a high frequency of head impacts leads to chronic cognitive deficits in the absence of key TBI or CTE pathology and we determine that these behavioral deficits are due to chronic adaptation of the excitatory synapse These data nominate synaptic adaptations as a potential mechanism for early abnormal behavioral events observed after repeated head impact and suggest that impacts below that required to generate neuropathological sequelae may still cause substantial neuronal dysfunction when delivered at a sufficient frequency

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