Abstract
Traumatic brain injury (TBI) and repetitive head impacts can result in a wide range of neurological symptoms. Despite being the most common neurological disorder in the world, repeat head impacts and TBI do not have any FDA-approved treatments. Single neuron modeling allows researchers to extrapolate cellular changes in individual neurons based on experimental data. We recently characterized a model of high frequency head impact (HFHI) with a phenotype of cognitive deficits associated with decreases in neuronal excitability of CA1 neurons and synaptic changes. While the synaptic changes have been interrogated in vivo, the cause and potential therapeutic targets of hypoexcitability following repetitive head impacts are unknown. Here, we generated in silico models of CA1 pyramidal neurons from current clamp data of control mice and mice that sustained HFHI. We use a directed evolution algorithm with a crowding penalty to generate a large and unbiased population of plausible models for each group that approximated the experimental features. The HFHI neuron model population showed decreased voltage gated sodium conductance and a general increase in potassium channel conductance. We used partial least squares regression analysis to identify combinations of channels that may account for CA1 hypoexcitability after HFHI. The hypoexcitability phenotype in models was linked to A- and M-type potassium channels in combination, but not by any single channel correlations. We provide an open access set of CA1 pyramidal neuron models for both control and HFHI conditions that can be used to predict the effects of pharmacological interventions in TBI models.
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Acknowledgments
This work was supported by RF1 NS107370 awarded to Mark P. Burns from the National Institute for Neurological Disorders and Stroke (NINDS). Rebekah C. Evans is supported by Georgetown University Medical Center start-up funds and BRAIN Initiative R00 NS112417 funded through NINDS. The NIH NINDS T32NS041218 training grant awarded to Center for Neural Injury and Recovery (CNIR) provided one year of stipend support for Daniel P. Chapman. NIH NINDS F30 NS122281-01A1 provided additional stipend support for Daniel P. Chapman.
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Rebekah Evans and Daniel P. Chapman conceptualized the project and came up with the experimental design. Daniel P. Chapman, wrote the code, analyzed the data, and wrote the first draft of the paper. Rebekah Evans, Mark P. Burns, and Stefano Vicini provided conceptual input on the project. All authors revised, edited, and approved the submitted version of the manuscript.
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Chapman, D.P., Vicini, S., Burns, M.P. et al. Single Neuron Modeling Identifies Potassium Channel Modulation as Potential Target for Repetitive Head Impacts. Neuroinform 21, 501–516 (2023). https://doi.org/10.1007/s12021-023-09633-7
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DOI: https://doi.org/10.1007/s12021-023-09633-7