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

Abstract

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 γ-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.

Differential contributions of somatic and dendritic calcium-dependent potassium currents to the control of motoneuron excitability following spinal cord injury

“…In order to do so, we assume values of conductances for the PICs, I CaL and I NaP that generate a counter-clockwise I-f hysteresis (Li and Bennett 2003;Li et al 2004a) such that the ratio of the I CaL and I NaP conductances are *1.772 as noted in (Li et al 2004a). Furthermore, we set the dendritic I KCaL to be a smaller fraction of I CaL as observed after chronic SCI (Li and Bennett 2007) (see (Venugopal et al 2011) and Discussion for further model considerations).…”

“…Thus the plateau can outlast somatic firing offset. The stability of the plateau further suggests that a motoneuron could remain depolarized and hence predisposed to begin firing at higher (tertiary) frequencies in response to a somatic/dendritic excitation that would otherwise cause no firing or low frequency firing (also see (Lee and Heckman 1998a, b;Venugopal et al 2011) for bistability). Hence, the firing offset and the plateau offset are distinct phenomena.…”

“…PIC activation may be facilitated by increased excitatory reflexes following spinal cord injury (Baker and Chandler 1987;Li et al 2004b). Synaptic inhibition has been shown to be a key mechanism in the control of motoneuron discharge and dendritic PIC activation (Bennett et al 1998;Hultborn et al 2003), particularly for dendritic sources of inhibition (Bui et al 2008;Venugopal et al 2011). Synaptic inhibition may be altered by changes in inhibitory receptors (Bareyre and Schwab 2003;Khristy et al 2009) and alterations in the strength of segmental inhibitory synaptic inputs (Shapiro 1997;Norton et al 2008).…”

“…Moreover, downregulation of the potassium-chloride cotransporter KCC2 following SCI depolarizes the chloride equilibrium potential and reduces the strength of synaptic inhibition (Boulenguez et al 2010). Thus changes in several mechanisms related to synaptic inhibition may contribute to motoneuron hyperexcitability and hyperreflexia and provide potential targets for therapeutic intervention (Venugopal et al 2011). …”

Differential Neuroprotective Effects of Interleukin-1 Receptor Antagonist on Spinal Cord Neurons after Excitotoxic Injury

“…In human SCI patients, dysfunction or loss of Renshaw cells is thought to cause loss of voluntary muscle control due to hypersensitization of motor neurons, and dysfunction of the motor neuron-Renshaw cell circuit has been proposed to be one of the mechanisms behind spasticity after spinal cord injury [42,43]. Our findings indicate that the early and extensive demise of Renshaw cells after excitotoxic secondary damage could at least in part be responsible for this pathophysiology.…”