Mechanisms regulating the specificity and strength of muscle afferent inputs in the spinal cord

Abstract

We investigated factors controlling the development of connections between muscle spindle afferents, spinal motor neurons and inhibitory Renshaw cells. Several mutants were examined to establish the role of muscle spindles, muscle spindle-derived NT3 and excess NT3 in determining the specificity and strength of these connections. The findings suggest that although spindlederived factors are not necessary for the initial formation and specificity of the synapses, spindlederived NT3 seems necessary for strengthening homonymous connections between Ia afferents and motor neurons during the second postnatal week. We also found evidence for functional monosynaptic connections between sensory afferents and neonatal Renshaw cells although the density of these synapses decreases at P15. We conclude that muscle spindle synapses are weakened on Renshaw cells while they are strengthened on motor neurons. Interestingly, the loss of sensory synapses on Renshaw cells was reversed in mice over-expresssing NT3 in the periphery, suggesting that different levels of NT3 are required for functional maintenance and strengthening of spindle afferent inputs on motor neurons and Renshaw cells.

Development of Twitching in Sleeping Infant Mice Depends on Sensory Experience

“…There are several reasons to believe that they might. First, agonist-antagonist twitches developed substantially in the WTs and Hets between P4 and P10, consistent with evidence that the monosynaptic reflex circuit strengthens over the early postnatal period [13, 14, 19]. Second, adult ErbB2 KOs exhibit deficient hindlimb extension reflexes as well as a near-complete absence of Ia afferent connections with spinal motoneurons [6, 8]; accordingly, if the stretch reflex were indeed triggered during twitching, one would expect that, of all four twitch pairs, the agonist-antagonist twitches would be most affected by the absence of muscle spindles, which was clearly the case.…”

“…High-speed videography of forelimb twitches unexpectedly revealed a category of reflex-like twitching—comprising an agonist twitch followed immediately by an antagonist twitch—that developed postnatally in wild types/heterozygotes but not in knockouts. Contrary to evidence from adults that spinal reflexes are inhibited during twitching [9–11], this finding suggests that twitches trigger the monosynaptic stretch reflex and, by doing so, contribute to its activity-dependent development [12–14]. Next, we assessed developmental changes in the frequency and organization (i.e., entropy) of more complex, multi-joint patterns of twitching; again, wild types/heterozygotes exhibited developmental changes in twitch patterning that were not seen in knockouts.…”

“…In fact, it has been suggested that the activity-dependent release of neurotrophin 3 by muscle spindles strengthens Ia afferent connections on motoneurons during the second postnatal week [13, 14]. Thus, in light of the early postnatal functional development of muscle spindles [21] and the monosynaptic stretch reflex [12–14], we propose twitching as a source of discrete activity for developing spinal circuits.…”

Enhancing Proprioceptive Input to Motoneurons Differentially Affects Expression of Neurotrophin 3 and Brain-Derived Neurotrophic Factor in Rat Hoffmann-Reflex Circuitry

“…It poses the question on the physiological implications of low-threshold proprioceptive stimulation for motoneuron excitability. Muscle spindle-derived NT-3 was found to be necessary for strengthening connections between Ia afferents and motoneurons during the early postnatal period [53], [54]. However, moderately increased levels of NT-3 in the spinal cord caused a decrease of input resistance of motoneurons, an increase of their threshold for discharge and decline of amplitude of EPSPs to maximal monosynaptic Ia stimuli [17] indicating that in mature rats NT-3 might attenuate motoneuron excitability.…”

Sensorimotor function is modulated by the serotonin receptor 1d, a novel marker for gamma motor neurons

“…Disturbed serotonin signaling affects cell survival (Stankovski et al, 2007), axon guidance (Haydon et al, 1984; Bonnin et al, 2007) and development of neural circuits in the spinal cord and cerebral cortex (Pflieger et al, 2002; Gaspar et al, 2003). Further more, muscle-derived signals are important for proper tuning of synaptic strength between Ia afferents and MNs (Frank and Wenner, 1993; Mentis et al, 2010). We found expression of the serotonin related genes Tph1 , Aadc and VMAT2 in muscle spindles of young mice, which may indicate that developing sensorimotor synapses are modulated by serotonin, and that this modulation may be disrupted in 5-ht1d −/− mutants.…”