Modulation of inhibitory strength and kinetics facilitates regulation of persistent inward currents and motoneuron excitability following spinal cord injury

Venugopal S, Hamm TM, Crook SM, Jung R. Modulation of inhibitory strength and kinetics facilitates regulation of persistent inward currents and motoneuron excitability following spinal cord injury. J Neurophysiol 106: 2167-2179, 2011. First published July 20, 2011; doi:10.1152/jn.00359.2011.-Spasticity is commonly observed after chronic spinal cord injury (SCI) and many other central nervous system disorders (e. g., multiple sclerosis, stroke). SCI-induced spasticity has been associated with motoneuron hyperexcitability partly due to enhanced activation of intrinsic persistent inward currents (PICs). Disrupted spinal inhibitory mechanisms also have been implicated. Altered inhibition can result from complex changes in the strength, kinetics, and reversal potential (E-Cl-) of gamma-aminobutyric acid A (GABA(A)) and glycine receptor currents. Development of optimal therapeutic strategies requires an understanding of the impact of these interacting factors on motoneuron excitability. We employed computational methods to study the effects of conductance, kinetics, and E-Cl- of a dendritic inhibition on PIC activation and motoneuron discharge. A two-compartment motoneuron with enhanced PICs characteristic of SCI and receiving recurrent inhibition from Renshaw cells was utilized in these simulations. This dendritic inhibition regulated PIC onset and offset and exerted its strongest effects at motoneuron recruitment and in the secondary range of the current-frequency relationship during PIC activation. Increasing inhibitory conductance compensated for moderate depolarizing shifts in E-Cl- by limiting PIC activation and self-sustained firing. Furthermore, GABA(A) currents exerted greater control on PIC activation than glycinergic currents, an effect attributable to their slower kinetics. These results suggest that modulation of the strength and kinetics of GABA(A) currents could provide treatment strategies for uncontrollable spasms.