VGLUT1 synapses and P‐boutons on regenerating motoneurons after nerve crush

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Excerpt

Peripheral nerve injuries may arise from a variety of trauma from nerve crush to complete lacerations, and affect different types of nerves and body regions. Although nerve regeneration occurs in the periphery, overall recovery of motor function is generally disappointing; only 10% of adult patients regain near‐normal function after median or ulnar injuries that require surgical repair, although outcomes are much better after milder injuries (Brushart, 2011; Lundborg, 2003). It is thus important to understand the neurobiological mechanisms that impair motor function recovery to different levels after different injuries.
Axon regeneration is fairly inefficient in patients with injuries in large nerves or that occur at long distances from their targets (e.g., a brachial plexus injury). One problem is that the velocity of peripheral axon regeneration is slow (1–3 mm/day) (Sunderland, 1947) and regeneration capacity declines with time (Fu & Gordon, 1995a, 1995b). In addition, pathfinding signals found in early development are not present in the adult and regenerating axons have difficulties finding the correct paths and can be misrouted to wrong muscles or targets (Allodi, Udina, & Navarro, 2012; Brushart & Mesulam, 1980; Brushart, Tarlov, & Mesulam, 1983). Not surprisingly, much experimental attention has focused on mechanisms that can improve the efficiency and specificity of regeneration in the periphery (Chan, Gordon, Zochodne, & Power, 2014; Gordon & English, 2016). However, even when successful peripheral regeneration is achieved after surgical repair, persistent motor deficits remain. For example, full nerve transection and repair of small distal nerves projecting to single hind limb muscles (medial gastrocnemius [MG] nerve or quadriceps nerves) result in rapid and specific muscle reinnervation and full recovery of force within weeks, but stretch reflexes are permanently lost. This occurs even though stretch‐sensitive sensory proprioceptors (i.e., Ia afferents) efficiently reinnervate muscle spindle receptors and are capable of encoding and transmitting information about muscle length (Bullinger, Nardelli, Pinter, Alvarez, & Cope, 2011; Cope, Bonasera, & Nichols, 1994; Haftel et al., 2005; Lyle, Prilutsky, Gregor, Abelew, & Nichols, 2016). Deficits in feedback information about muscle length manifest in abnormal inter‐joint coordination during walking, higher than normal co‐contraction of antagonists around single joints and errors in slope walking (Abelew, Miller, Cope, & Nichols, 2000; Maas, Prilutsky, Nichols, & Gregor, 2007; Sabatier, To, Nicolini, & English, 2011). Some of these deficits are compensated by adjustments in the unaffected hind limb joints such that overall limb kinematics and general limb functions are preserved (Chang, Auyang, Scholz, & Nichols, 2009). However, feedback information about muscle length has many important roles during ongoing motor activity including opposing influences from force signals generated by Ib Golgi tendon organs in nearby muscles (Lyle et al., 2016). Their loss implies that tasks involving high forces and/or rapid and large muscle lengthening (steep downslopes) should predictably show significant deficits in performance after nerve regeneration (Abelew et al., 2000; Lyle et al., 2016; Maas et al., 2007).
Deficits in proprioceptive information relayed by stretch‐encoding Ia afferents arise because their central synaptic arbors inside the spinal cord are removed from the ventral horn (Alvarez, Bullinger, Titus, Nardelli, & Cope, 2010; Alvarez et al., 2011; Bullinger et al., 2011). This causes the loss of most synaptic collaterals from Ia afferents in lamina IX, and to lesser extent those in lamina VII, greatly denervating motoneurons. Motoneurons lose approximately 60–65% of synapses from Ia afferents on the dendritic arbor and 85–90% on the cell bodies (Rotterman, Nardelli, Cope, & Alvarez, 2014).
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