Changes in Hippocampal Synaptic Plasticity Following Exposure to High Frequency Head Impacts (HF-HI)

Abstract

Concussions account for over 80% of all cases of TBI reported each year. Sustaining multiple concussions is associated with the development of lasting cognitive and memory impairments. Chronic traumatic encephalopathy (CTE), a slowly developing tauopathy, has been linked to the development of these impairments; however, it is unknown if the cognitive deficits associated with CTE can occur prior to the deposition of tau and death of neuronal cells. The overarching goal of these studies was therefore to 1) identify any tau-independent mechanisms associated with deficit development following exposure to multiple concussive impacts and 2) to assess how injury frequency contributes to deficit development.

To perform these studies, our group has developed an experimental model of high frequency head impacts (HF-HI), where mice receive 5 hits a day for 6 days (30 hits total). It recapitulates the frequency of injuries experienced by athletes engaged in high contact sports like football and boxing. Immunohistochemical analyses revealed that HF-HI did not cause cell death, inflammation, tau accumulation or excitatory synapse loss compared to sham mice. Despite this, behavioral testing at one-month post injury showed that HF-HI results in deficits in hippocampal-dependent learning and memory. I hypothesized that synaptic adaptations resulting from HF-HI were underlying the development of the deficits. To assess synaptic plasticity, I measured long-term potentiation via stimulation of the Schaffer collateral pathway, as this has been described as the cellular mechanism underlying learning and memory. I discovered a significant impairment in LTP despite there being no difference in their stimulus input/output curve. Whole cell patch clamp electrophysiology was then done on individual CA1 pyramidal neurons at 24 hours and 1 month after HF-HI. Current clamp experiments revealed differences in intrinsic cellular properties and excitability 24 hours post impacts, which resolved after 1 month. Voltage clamp experiments revealed that NMDA receptor contributions to excitatory post synaptic currents were increased at 24 hours and 1 month after impacts, reinforcing the hypothesis that synaptic adaptations related to plasticity occur following HF-HI. Taken together, these changes illustrate that postsynaptic modifications to glutamatergic receptors arise following HF-HI, and are sufficient to alter plasticity, learning and memory.