IMPAIRED INTRINSIC EXCITABILITY OF REMOTE NEURONS AFTER SPINAL CORD INJURY

Spinal cord injury (SCI) causes long-lasting motor deficits not only due to local damage but also through secondary alterations in remote brain regions connected to the lesion, including the motor cortex (M1) and the red nucleus (RN). These motor impairments arise in part from disrupted neuronal function in supraspinal motor circuits. Specifically, reduced intrinsic excitability limits the ability of neurons to generate action potentials, weakening motor commands even when excitatory synaptic input is preserved.
Here, we investigated SCI’s impact on intrinsic excitability and synaptic transmission in supraspinal neurons during acute and chronic phases. Using a mouse model, we performed ex vivo whole-cell patch-clamp recordings in RN and M1 at 7, 28, and 60 days post-injury. Current-clamp recordings assessed intrinsic membrane properties and action potential firing, while voltage-clamp recordings measured spontaneous excitatory postsynaptic currents (sEPSCs).
Current-clamp analyses revealed a progressive reduction in intrinsic excitability following SCI, peaking at 28 days. Injured neurons showed enhanced hyperpolarizing responses and reduced action potential firing, while resting membrane potential remained largely unaffected. Voltage-clamp recordings showed no significant changes in sEPSC frequency or amplitude, suggesting preserved excitatory synaptic input.
Crucially, this electrophysiological profile was associated with increased phosphorylation of AMP-activated protein kinase (p-AMPK), which in turn modulates the activity of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. HCN channels mediate the inward depolarizing current I_h and are critical for setting neuronal responsiveness to synaptic inputs.
Overall, SCI induces metabolic and intrinsic alterations in axotomized neurons, potentially limiting their regenerative capacity and functional reconnection.