Zain Syed

Background: Traumatic brain injury (TBI), resulting from an impact to the head, leads to impairments in neurological function that can be temporary or permanent.¹ A case of TBI is classified as severe, moderate, or mild, if assigned a Glasgow Coma Scale score of 3-9, 9-12, or 13-15, respectively.² However, mild TBI (mTBI) is the most common, representing more than 80% of cases.³ mTBI is often caused by the head’s exposure to repetitive impacts from weak mechanical forces.^1,2,3 Furthermore, when mTBI is associated with this etiology, it is typically known as repeated mild TBI (rmTBI).^1,2,3,4 Individuals participating in contact sports, such as American football and boxing, are noted to be at a higher risk for developing mTBI.^1,2,3 Presentation of mTBI is characterized by cognitive symptoms, including confusion, impaired consciousness, and memory deficits.^2,3,4 The pathogenesis of memory impairment in mTBI consists of two phases: an acute phase lasting 24-hours post-impact and a chronic phase commencing 1-month post-impact.⁵ The acute phase is characterized by excess glutamate release from pre-synaptic CA3 neuronal terminals. However, a cardinal feature of both phases is a dampened long-term potentiation (LTP) response at CA3-CA1 synapses.⁵ Diagnosis of mTBI requires knowing the mechanism of injury, patient status preceding injury, and the cognitive signs/symptoms of the patient.⁴ Among the treatment options for mTBI are cognitive rehabilitation, neuromodulation techniques (e.g., transcranial magnetic stimulation), implementation of exoskeletons, and – infrequently – pharmacological treatment.⁴

Objective: This narrative explores the pathological changes associated with memory impairment in mTBI and discusses a promising therapeutic intervention.

Search Methods: An online search was performed in the PubMed database from 2018 to 2023 using the following keywords: “traumatic brain injury”, “synaptic plasticity”, “hippocampus”.

Methods/Results: A closed-head drop model was used to induce rmTBI.⁵ Mice underwent a high-frequency head impact (HF-HI) schedule, consisting of five successive impacts per day for six days.⁵ Impacts were at a depth of 7.5mm and a rate of 2.35m/s. Field excitatory post-synaptic potentials (fEPSPs) were measured using stimulating and recording electrodes.⁵ Action potential (AP) frequency was measured via injections of hyperpolarizing and depolarizing currents.⁵ T-maze and Barnes maze tests were used for the cognitive assessment of mice to determine general brain function following HF-HI.⁵ To examine the role of glutamate-mediated excitotoxicity, memantine was administered to mice before undergoing the HF-HI protocol.⁵ The following changes were found in CA1 neurons during the acute phase: (I) decreased AMPA/NMDA receptor ratio, (II) decreased fEPSPs, and (III) decreased AP frequency.⁵ Acute phase behavioral changes included: (IV) decreased spontaneous alterations in the T-maze and (V) decreased entries into the escape target area in the Barnes maze.⁵ (I), (II), and (IV) persisted into the chronic phase.⁵ Memantine treatment preceding HF-HI increased AMPA/NMDA receptor ratio and improved memory function in the Barnes maze test.⁵

Conclusions: Due to elevated glutamate levels immediately following mTBI, AMPA receptors are downregulated on CA1 pyramidal neurons.⁵ This effect is likely a neuroprotective measure to prevent excitotoxicity, but also a principal contributor to diminished LTP at CA3-CA1 synapses, ultimately leading to memory impairment.⁵ Furthermore, prophylactic memantine treatment can provide therapeutic benefits by inhibiting the excitotoxic effects that contribute to weakened hippocampal connectivity.⁵

Works Cited:

1. Jamjoom AAB, Rhodes J, Andrews PJD, Grant SGN. The synapse in traumatic brain injury. Brain. 2021;144(1):18-31. doi:10.1093/brain/awaa321
2. Graham NS, Sharp DJ. Understanding neurodegeneration after traumatic brain injury: from mechanisms to clinical trials in dementia. J Neurol Neurosurg Psychiatry. 2019;90(11):1221-1233. doi:10.1136/jnnp-2017-317557
3. Luo Y, Zou H, Wu Y, Cai F, Zhang S, Song W. Mild traumatic brain injury induces memory deficits with alteration of gene expression profile. Sci Rep. 2017;7(1):10846. Published 2017 Sep 7. doi:10.1038/s41598-017-11458-9
4. Marklund N, Bellander BM, Godbolt AK, Levin H, McCrory P, Thelin EP. Treatments and rehabilitation in the acute and chronic state of traumatic brain injury. J Intern Med. 2019;285(6):608-623. doi:10.1111/joim.12900
5. Sloley SS, Main BS, Winston CN, et al. High-frequency head impact causes chronic synaptic adaptation and long-term cognitive impairment in mice. Nat Commun. 2021;12(1):2613. Published 2021 May 10. doi:10.1038/s41467-021-22744-6