Depolarization and Hyperexcitability of Cortical Motor Neurons after Spinal Cord Injury Associates with Reduced HCN Channel Activity

Int. J. Mol. Sci., 2023 · DOI: 10.3390/ijms24054715 · Published: March 1, 2023

Simple Explanation

A spinal cord injury (SCI) damages the nerve fibers (axons) of brain cells (neurons) in the neocortex. This damage changes how easily these brain cells can be excited (cortical excitability). This results in abnormal activity and output of the infragranular cortical layers. The study found that the principal neurons of the primary motor cortex layer V (M1LV), which are damaged after SCI, become more easily excitable (hyperexcitable) following the injury. This led the researchers to investigate the role of hyperpolarization cyclic nucleotide gated channels (HCN channels) in this process. The research suggests that dysfunction of HCN channels contributes to the issues in axotomized M1LV neurons after spinal cord injury, but this contribution varies among neurons and occurs alongside other mechanisms.

Study Duration

1 week

Participants

Female Fisher-344 rats of 12 weeks of age

Evidence Level

Not specified

Key Findings

1
Axotomized M1LV neurons became excessively depolarized after SCI, meaning their resting membrane potential was higher than normal.
2
In these depolarized cells, HCN channels were less active and less effective at controlling neuronal excitability because the membrane potential was outside the range where HCN channels normally operate.
3
Blocking HCN channels with a drug (ZD7288) had different effects depending on how depolarized the neurons were. It only helped neurons that were not already excessively depolarized.

Research Summary

This study investigates the consequences of axotomy on the function of principal neurons of the primary motor cortex layer V (M1LV) in a rat model of SCI. Transection of the dorsal corticospinal tract (CST) was carried out at the cervical level. The study found that SCI did not affect the intrinsic properties of HCN channels in M1LV neurons per se. However, a striking pathophysiological feature after SCI was the chronic RMP depolarization in some neurons, which reached values beyond the voltage range of HCN channel activation. The selective blocker ZD7288 modulated the activity of axotomized SCIHP neurons, hyperpolarizing their RMP and decreasing their intrinsic excitability. For the opposite situation, ZD7288 failed to hyperpolarize the RMP and failed to decrease the hyperexcitability of SCIDP neurons.

Practical Implications

Pharmacological Targeting

HCN channels may be potential targets for pharmacological interventions to modulate cortical excitability after SCI, but careful consideration is needed due to their complex role.

Personalized Treatment

Treatment strategies should account for the heterogeneous responses of neurons to HCN channel modulation, particularly the degree of depolarization.

Timing Considerations

The effects of HCN channel modulation may vary over time after SCI due to fluctuating levels of cortical disinhibition.

Study Limitations

1
The study focused on a specific time point (one week after SCI), and the long-term effects of HCN channel dysfunction remain unclear.
2
The study used a rat model of SCI, and the findings may not be directly applicable to humans.
3
The molecular components that cause chronic depolarization of M1LV neurons remain to be determined.

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