Search

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.

The mean location of Renshaw synapses on spinal motoneurons and their synaptic conductance were estimated from changes in impedance magnitude produced by sustained recurrent inhibition. Motoneuron impedance was determined by injecting quasi-white noise current into lumbosacral motoneurons of pentobarbital-anesthetized cats. Synaptic location and conductance were estimated by comparing observed impedance changes to simulation results obtained using standard motoneuron models and compartmental models fit to each impedance function. Estimated synaptic locations ranged from 0.10 to 0.41lambda, with a mean of 0.19 or 0.24lambda, depending on the estimation method. Average dendritic path length was 262 microm. Average synaptic conductance was 23 to 27 nS (range: 6.7 to 57.9 nS), corresponding to conductance changes of 78 to 88% of resting membrane conductance. Estimated accuracy was supported by consistency using different estimation methods, agreement with Fyffe's 1991 morphological data, and comparisons of observed and simulated recurrent IPSP amplitudes. Synaptic location, but not synaptic conductance, was correlated with rheobase, a measure of motoneuron excitability. Synaptic conductance did not depend on synaptic location. A regression analysis demonstrated that synaptic conductance and cell impedance were the principal factors determining recurrent IPSP amplitude. Simulations using the observed values and locations of Renshaw conductance demonstrate that recurrent inhibition can require as much as an additional 14 to 18% sustained excitatory synaptic conductance to depolarize motoneurons sufficiently to activate somatic or dendritic inward currents and recruit motoneurons or amplify excitatory synaptic currents.

The incidence of recurrent inhibition and facilitation in motor nuclei innervating the dorsiflexors of the ankle and digits was examined in spinalized, decerebrate cats. Motoneurons innervating the anterior and posterior portions of the tibialis anterior (TAa and TAp, respectively) received strong recurrent inhibition following stimulation of either of the homonymous muscle nerves. Both motoneuron species received substantial recurrent inhibition from the semitendinosus (St), but stimulation of the nerve to the extensor digitorum longus (EDL), an ankle flexor synergist, evoked smaller recurrent IPSPs. TA motoneurons received mainly facilitation from hindlimb extensors of the hip and ankle. Motoneurons of the EDL and extensor digitorum brevis (EDB), synergists which share mechanical action at the metatarsophalangeal joint and the digits, received little recurrent inhibition in response to stimulation of the nerve to either muscle. Overall, stimulation of heteronymous flexor nerves (including TAa, TAp, and St) failed to evoke responses in most of the EDB and EDL neurons tested (50-83%), and the amplitude of recurrent inhibitory responses was small. Recurrent facilitation from the extensors was more common in these motor nuclei. Most responses recorded in EDB motoneurons following either flexor or extensor nerve stimulation were recurrent facilitations. The sensitivity of this facilitation in EDB motoneurons to injection of polarizing current and its central latency indicate that it is mediated by a disinhibitory, trisynaptic pathway. Stimulation of the nerve to EDB produced recurrent IPSPs in some flexor motoneurons, but these potentials were infrequent and their amplitude was usually small. Based on a comparison of the distribution of recurrent inhibition to published reports of the activities of TAa, TAp, EDL, and EDB during different forms of locomotion, we conclude that recurrent inhibition is large for motor nuclei that exhibit stereotypical activity, while motor nuclei that are activated independently receive and produce little recurrent inhibition. Despite the absence of recurrent inhibition in some motor nuclei, recurrent circuits may still participate in their control through disinhibitory, facilitatory mechanisms.

1. The amplitude of recurrent inhibitory postsynaptic potentials (RIPSPs) was examined in pairs of lumbosacral motoneurons that were separated by a known distance and were identified by antidromic stimulation of muscle nerves. One motoneuron was stimulated by injecting depolarizing current pulses, and postsynaptic responses were recorded and averaged in the second motoneuron. Input resistance, rheobase, and conduction velocity were determined for many motoneurons. Most motoneurons innervated extensor muscles. 2. RIPSP values as large as -283 microV were recorded, but most were between -10 and -40 microV. RIPSPs from individual motoneurons of a pool are distributed to several heteronymous motor nuclei and have a range of amplitudes comparable with homonymous RIPSPs. 3. A specific spatial distribution of RIPSP amplitudes was found whereby the largest RIPSP amplitudes (> 40 microV) occurred in motoneurons located within +/- 1.4 mm of the stimulated motoneuron. A significant correlation was found between RIPSP amplitude and the distance between motoneurons for all motoneuron pairs. This correlation was also found within individual groups of motoneuron pairs that innervate the lateral gastrocnemius, medial gastrocnemius, anterior-middle biceps femoris, or soleus muscles. 4. The dependency of RIPSP amplitude on the motoneuron species, which is the particular muscle a motoneuron innervates, is less distinct than the dependency of RIPSP amplitude on topography. Pooling all motoneuron species of close motoneuron pairs indicated that RIPSPs measured in homonymous motoneuron pairs were greater in amplitude than RIPSPs measured in heteronymous pairs. In addition, homonymous RIPSPs of anterior middle biceps femoris or lateral gastrocnemius motoneurons were greater than heteronymous RIPSPs of those motoneurons in all heteronymous combinations. However, homonymous and heteronymous RIPSPs were not significantly different when heteronymous pairs were restricted to individual combinations of species. These findings indicate that RIPSP amplitudes within a set of motor nuclei interconnected by recurrent inhibition are dependent in some cases on the species of motoneurons, but this effect is less important than the effect of topography on RIPSP amplitude. 5. These results indicate that recurrent inhibition in motoneuron pools that innervate hindlimb extensor muscles has a strong topographic organization, such that the strongest recurrent inhibition is produced by each motoneuron in a restricted rostrocaudal zone that includes both homonymous and heteronymous motor nuclei. This suggests that recurrent inhibition is organized for the control of several motor nuclei engaged in common motor activity as well as regulation of activity within individual motor pools.

1. Recurrent inhibitory postsynaptic potentials (IPSPs) to and from motoneurons innervating the flexor digitorum longus (FDL) and flexor hallucis longus (FHL) muscles of the cat were investigated to determine whether recurrent inhibitory projections involving these motoneurons are similar--as would be consistent with the Ia and anatomic synergism of FDL and FHL--or are dissimilar, as are the activities of these muscles during locomotion (O'Donovan et al. 1982). 2. Composite recurrent IPSPs were recorded in several species of motoneurons innervating hindlimb muscles in response to stimulation of a number of muscle nerves in cats allowed to become unanesthetized after ischemic decapitation. 3. No recurrent IPSPs from stimulation of the FDL nerve were observed in motoneurons innervating FDL, FHL, lateral gastrocnemius-soleus (LG-S), medial gastrocnemius (MG), plantaris (Pl), tibialis anterior (TA), or extensor digitorum longus (EDL). 4. The recurrent IPSPs produced by stimulation of FHL were larger and found more frequently in LG-S than in FDL motoneurons. Recurrent inhibition from FHL was also greater in Pl than in FDL motoneurons. 5. The recurrent IPSPs produced by stimulation of LG-S, PL, and MG were larger in FHL than in FDL motoneurons, and those from LG-S and MG were found more frequently in FHL than in FDL motoneurons. 6. Stimulation of the TA nerve produces recurrent IPSPs in FDL but not in FHL motoneurons. A few FDL and FHL cells (6 of 23 and 9 of 34, respectively) received small (less than 0.5 mV) recurrent IPSPs from stimulation of the EDL nerve.(ABSTRACT TRUNCATED AT 250 WORDS)

In anaesthetized cats, medial gastrocnemius motor units (MUs) were electrically stimulated via their ventral-root axons with independent random patterns. Isometric muscle tension and homonymous alpha-motoneuron (MN) membrane-potential fluctuations in response to these stimuli were recorded simultaneously, usually for periods of about 2 min. The tension and membrane potential were averaged with respect to a stimulus train over two disjoint time intervals, one stretching 20-40 s at record beginning, and the other a similar duration at the end of recording. Whereas average MU twitch amplitudes usually decreased between these periods, average membrane potential trajectories did not do so, such that, when normalized to the change in twitch amplitude, the membrane potential trajectories usually increased in size. This suggests that the decline in the mechanical effect of MU activation was accompanied by an increase in the gain of the afferent pathway to homonymous MNs, which was confirmed by gain computations in the frequency domain. This compensation could be a mechanism to maintain the high quality of information about MU contractions transmitted to MNs in the course of MU fatigue.