Nerve Terminal Degeneration Is Independent of Muscle Fiber Genotype in SOD1G93A Mice

Background: Motor neuron degeneration in SOD1 G93A transgenic mice begins at the nerve terminal. Here we examine whether this degeneration depends on expression of mutant SOD1 in muscle fibers. Methodology/Principal Findings: Hindlimb muscles were transplanted between wild-type and SOD1 G93A transgenic mice and the innervation status of neuromuscular junctions (NMJs) was examined after 2 months. The results showed that muscles from SOD1 G93A mice did not induce motor terminal degeneration in wildtype mice and that muscles from wildtype mice did not prevent degeneration in SOD1 G93A transgenic mice. Control studies demonstrated that muscles transplanted from SOD1 G93A mice continued to express mutant SOD1 protein. Experiments on wildtype mice established that the host supplied terminal Schwann cells (TSCs) at the NMJs of transplanted muscles. Conclusions/Significance: These results indicate that expression of the mutant protein in muscle is not needed to cause motor terminal degeneration in SOD1 G93A transgenic mice and that a combination of motor terminals, motor axons and Schwann cells, all of which express mutant protein may be sufficient

Movement Reduces the Dynamic Response of Muscle Spindle Afferents and Motoneuron Synaptic Potentials in Rat

Among the mechanisms that may result in modulation of the stretch reflex by the recent history of muscle contraction is the history dependence observed under some conditions in the response properties of muscle spindles. The present study was designed to test one report that in successive trials of muscle stretch-release, spindle afferent firing during stretch, i.e., the dynamic response shows no history dependence beyond the initial burst of firing at stretch onset. Firing responses of spindle afferents were recorded during sets of three consecutive trials of triangular stretch-release applied to triceps surae muscles in barbiturate-anesthetized rats. All 69 spindle afferents fired more action potentials (spikes) during the dynamic response of the first trial, excluding the initial burst, than in the following two trials. The reduced dynamic response (RDR) was nearly complete after trial 1 and amounted to an average of ∼12 fewer spikes (16 pps slower firing rate) in trial 3 than in trial 1. RDR was sensitive to the interval between stretch sets but independent of stretch velocity (4–32 mm/s). RDR was reflected in the synaptic potentials recorded intracellularly from 16 triceps surae α-motoneurons: depolarization during muscle stretch was appreciably reduced after trial 1. These findings demonstrate history dependence of spindle afferent responses that extends throughout the dynamic response in successive muscle stretches and that is synaptically transmitted to motoneurons with the probable effect, unless otherwise compensated, of modulating the stretch reflex

Movement Reduces the Dynamic Response of Muscle Spindle Afferents and Motoneuron Synaptic Potentials in Rat

Among the mechanisms that may result in modulation of the stretch reflex by the recent history of muscle contraction is the history dependence observed under some conditions in the response properties of muscle spindles. The present study was designed to test one report that in successive trials of muscle stretch-release, spindle afferent firing during stretch, i.e., the dynamic response shows no history dependence beyond the initial burst of firing at stretch onset. Firing responses of spindle afferents were recorded during sets of three consecutive trials of triangular stretch-release applied to triceps surae muscles in barbiturate-anesthetized rats. All 69 spindle afferents fired more action potentials (spikes) during the dynamic response of the first trial, excluding the initial burst, than in the following two trials. The reduced dynamic response (RDR) was nearly complete after trial 1 and amounted to an average of ∼12 fewer spikes (16 pps slower firing rate) in trial 3 than in trial 1. RDR was sensitive to the interval between stretch sets but independent of stretch velocity (4–32 mm/s). RDR was reflected in the synaptic potentials recorded intracellularly from 16 triceps surae α-motoneurons: depolarization during muscle stretch was appreciably reduced after trial 1. These findings demonstrate history dependence of spindle afferent responses that extends throughout the dynamic response in successive muscle stretches and that is synaptically transmitted to motoneurons with the probable effect, unless otherwise compensated, of modulating the stretch reflex

Movement Reduces the Dynamic Response of Muscle Spindle Afferents and Motoneuron Synaptic Potentials in Rat

Among the mechanisms that may result in modulation of the stretch reflex by the recent history of muscle contraction is the history dependence observed under some conditions in the response properties of muscle spindles. The present study was designed to test one report that in successive trials of muscle stretch-release, spindle afferent firing during stretch, i.e., the dynamic response shows no history dependence beyond the initial burst of firing at stretch onset. Firing responses of spindle afferents were recorded during sets of three consecutive trials of triangular stretch-release applied to triceps surae muscles in barbiturate-anesthetized rats. All 69 spindle afferents fired more action potentials (spikes) during the dynamic response of the first trial, excluding the initial burst, than in the following two trials. The reduced dynamic response (RDR) was nearly complete after trial 1 and amounted to an average of ∼12 fewer spikes (16 pps slower firing rate) in trial 3 than in trial 1. RDR was sensitive to the interval between stretch sets but independent of stretch velocity (4–32 mm/s). RDR was reflected in the synaptic potentials recorded intracellularly from 16 triceps surae α-motoneurons: depolarization during muscle stretch was appreciably reduced after trial 1. These findings demonstrate history dependence of spindle afferent responses that extends throughout the dynamic response in successive muscle stretches and that is synaptically transmitted to motoneurons with the probable effect, unless otherwise compensated, of modulating the stretch reflex

Rat Motoneuron Properties Recover Following Reinnervation in the Absence of Muscle Activity and Evoked Acetylcholine Release

Available evidence supports the idea that muscle fibres provide retrograde signals that enable the expression of adult motoneuron electrical properties but the mechanisms remain unknown. We showed recently that when acetylcholine receptors are blocked at motor endplates, the electrical properties of rat motoneurons change in a way that resembles changes observed after axotomy. This observation suggests that receptor blockade and axotomy interrupt the same signalling mechanisms but leaves open the possibility that the loss of muscle fibre activity underlies the observed effects. To address this issue, we examined the electrical properties of axotomized motoneurons following reinnervation. Ordinarily, these properties return to normal following reinnervation and re-activation of muscle, but in this study muscle fibre activity and evoked acetylcholine release were prevented during reinnervation by blocking axonal conduction. Under these conditions, the properties of motoneurons that successfully reinnervated muscle fibres recovered to normal despite the absence of muscle fibre activity and evoked release. We conclude that the expression of motoneuron electrical properties is not regulated by muscle fibre activity but rather by a retrograde signalling system coupled to activation of endplate acetylcholine receptors. Our results indicate that spontaneous release of acetylcholine from regenerated motor terminals is sufficient to operate the system

Rat Motoneuron Properties Recover Following Reinnervation in the Absence of Muscle Activity and Evoked Acetylcholine Release

Available evidence supports the idea that muscle fibres provide retrograde signals that enable the expression of adult motoneuron electrical properties but the mechanisms remain unknown. We showed recently that when acetylcholine receptors are blocked at motor endplates, the electrical properties of rat motoneurons change in a way that resembles changes observed after axotomy. This observation suggests that receptor blockade and axotomy interrupt the same signalling mechanisms but leaves open the possibility that the loss of muscle fibre activity underlies the observed effects. To address this issue, we examined the electrical properties of axotomized motoneurons following reinnervation. Ordinarily, these properties return to normal following reinnervation and re-activation of muscle, but in this study muscle fibre activity and evoked acetylcholine release were prevented during reinnervation by blocking axonal conduction. Under these conditions, the properties of motoneurons that successfully reinnervated muscle fibres recovered to normal despite the absence of muscle fibre activity and evoked release. We conclude that the expression of motoneuron electrical properties is not regulated by muscle fibre activity but rather by a retrograde signalling system coupled to activation of endplate acetylcholine receptors. Our results indicate that spontaneous release of acetylcholine from regenerated motor terminals is sufficient to operate the system

Central Suppression of Regenerated Proprioceptive Afferents

Long after a cut peripheral nerve reinnervates muscle and restores force production in adult cats, the muscle does not respond reflexively to stretch. Motivated by the likelihood that stretch areflexia is related to problems with sensing and controlling limb position after peripheral neuropathies, we sought to determine the underlying mechanism. Electrophysiological and morphological measurements were made in anesthetized rats having one of the nerves to the triceps surae muscles either untreated or cut and immediately rejoined surgically many months earlier. First, it was established that reinnervated muscles failed to generate stretch reflexes, extending observations of areflexia to a second species. Next, multiple elements in the sensorimotor circuit of the stretch reflex were examined in both the PNS and CNS. Encoding of muscle stretch by regenerated proprioceptive afferents was remarkably similar to normal, although we observed some expected abnormalities, e.g., increased length threshold. However, the robust stretch-evoked sensory response that arrived concurrently at the CNS in multiple proprioceptive afferents produced synaptic responses that were either smaller than normal or undetectable. Muscle stretch failed to evoke detectable synaptic responses in 13 of 22 motoneurons, although electrical stimulation generated monosynaptic excitatory postsynaptic potentials that were indistinguishable from normal. The ineffectiveness of muscle stretch was not attributable therefore to dysfunction at synapses made between regenerated Ia afferents and motoneurons. Among multiple candidate mechanisms, we suggest that centrally controlled neural circuits may actively suppress the sensory information encoded by regenerated proprioceptive afferents to prevent recovery of the stretch reflex