The relationship of intramuscular nerve branching and synaptogenesis to motoneuron survival

GABAergic and glycinergic synaptic transmission is proposed to promote the maturation and refinement of the developing CNS. Here we provide morphological and functional evidence that glycinergic and GABAergic synapses control motoneuron development in a regionspecific manner during programmed cell death. In gephyrin-deficient mice that lack all postsynaptic glycine receptor and some GABA A receptor clusters, there was increased spontaneous respiratory motor activity, reduced respiratory motoneuron survival, and decreased innervation of the diaphragm. In contrast, limb-innervating motoneurons showed decreased spontaneous activity, increased survival, and increased innervation of their target muscles. Both GABA and glycine increased limb-innervating motoneuron activity and decreased respiratory motoneuron activity in wild-type mice, but only glycine responses were abolished in gephyrin-deficient mice. Our results provide genetic evidence that the development of glycinergic and GABAergic synaptic inputs onto motoneurons plays an important role in the survival, axonal branching, and spontaneous activity of motoneurons in developing mammalian embryos.

Section: Skeletal Muscle Activity Regulates Motoneuron Development Insupporting

confidence: 89%

Glycinergic and GABAergic Synaptic Activity Differentially Regulate Motoneuron Survival and Skeletal Muscle Innervation

Banks

Kanjhan²,

Wiese³

et al. 2005

“…Moreover, in embryos continuously exposed to nicotine until 120 hpf, the axons of secondary motoneurons are also severely stunted (data not shown). These results are in stark contrast to the anatomy of motoneurons of zebrafish paralytic mutants, in which motoneuron axons appear normal, and to motoneurons of the developing chick, in which the axons are actually hyperbranched when muscle activity is blocked (Pittman and Oppenheim, 1979;Westerfield et al, 1990;Landmesser, 1992;Ono et al, 2001). This provides yet another line of evidence suggesting a neuronal mechanism for the action of nicotine in embryonic/ larval zebrafish.…”

Section: Nicotine Alters Axonal Pathfinding In Zebrafish Embryos: a Ncontrasting

confidence: 76%

Nicotinic Receptors Mediate Changes in Spinal Motoneuron Development and Axonal Pathfinding in Embryonic Zebrafish Exposed to Nicotine

Svoboda

Vijayaraghavan²,

Tanguay

2002

We show that transient exposure of embryonic zebrafish to nicotine delays the development of secondary spinal motoneurons. Furthermore, there is a long-lasting alteration in axonal pathfinding in secondary motoneurons that is not ameliorated by drug withdrawal. These effects of nicotine were reversed by mammalian nicotinic receptor antagonists. Coupled with these changes is a long-term alteration in swimming behavior. Our results show that transient embryonic exposure to nicotine leads to long-lasting effects on the vertebrate nervous system. These results also demonstrate that the zebrafish is a useful model to examine the effects of nicotine specifically, and drugs of abuse in general, on the development of the CNS in vertebrates.

“…However, the fact that both large-and smallsized facial MNs were retrogradely labeled indicates that the rescued MNs must have axons in close proximity to the whiskerpad muscles and that even the small-sized axons have an intact retrograde transport system. It is interesting that whereas the complete rescue of MNs from developmental PCD by neuromuscular activity blockade in avian and mammalian embryos results in a striking increase in intramuscular axon branching and synapse numbers (Landmesser, 1992;Misgeld et al, 2002;Brandon et al, 2003), this was not the case in Bax KO/or MyoGDNF embryos (data not shown).…”

Section: Resultsmentioning

confidence: 92%

“…Previous studies of motor systems developing with reduced PCD have reported more cell bodies in central motor nuclei or more axons in cranial or spinal roots , but with the exception of paralytic chicks and mice (Ding et al, 1983;Oppenheim and Chu-Wang, 1983;Landmesser, 1992;Misgeld et al, 2002), whether rescued MNs project to their muscle targets has not been systematically examined Jacob et al, 2005). In cross sections of adult peripheral hindlimb and cranial nerves (mixed motor and sensory) of Bax KO and MyoGDNF mice (and in the paralyzed embryonic chick), we observed more (ϳ 40 -50%) myelinated axons in close proximity to their muscles compared with WT mice or vehicle-treated chick embryos (Table 1, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Neither MyoGDNF nor Bax KO mice exhibit the striking increases in intramuscular axon branching or in the number of synapses on individual extrafusal myofibers observed after activity blockade in chick and mouse embryos (Ding et al, 1983;Oppenheim and Chu-Wang, 1983;Oppenheim, 1984;Oppenheim et al, 1986;Hall et al, 1988;Landmesser, 1992;Tang and Landmesser, 1993;Misgeld et al, 2002;Brandon et al, 2003). This difference may be attributable to the MNs rescued by activity blockade having greater access to muscle-derived trophic support for promoting branching and synaptogenesis (Landmesser, 1992;Oppenheim et al, 2003). In all of the models examined here, MNs rescued from PCD only completed their differentiation when there was an associated direct or indirect phenotypic change in target muscle.…”

Section: Neuromuscular Development After Mn Rescue By Activity Blockadementioning

confidence: 99%

See 1 more Smart Citation

Neuromuscular Development in the Absence of Programmed Cell Death: Phenotypic Alteration of Motoneurons and Muscle

Buss

Gould²,

Ma³

et al. 2006

The widespread, massive loss of developing neurons in the central and peripheral nervous system of birds and mammals is generally considered to be an evolutionary adaptation. However, until recently, models for testing both the immediate and long-term consequences of preventing this normal cell loss have not been available. We have taken advantage of several methods for preventing neuronal death in vivo to ask whether rescued neurons [e.g., motoneurons (MNs)] differentiate normally and become functionally incorporated into the nervous system. Although many aspects of MN differentiation occurred normally after the prevention of cell death (including the expression of several motoneuron-specific markers, axon projections into the ventral root and peripheral nerves, ultrastructure, dendritic arborization, and afferent axosomatic synapses), other features of the neuromuscular system (MNs and muscle) were abnormal. The cell bodies and axons of MNs were smaller than normal, many MN axons failed to become myelinated or to form functional synaptic contacts with target muscles, and a subpopulation of rescued cells were transformed from ␣-to ␥-like MNs. Additionally, after the rescue of MNs in myogenin glial cell line-derived neurotrophic factor (MyoGDNF) transgenic mice, myofiber differentiation of extrafusal skeletal muscle was transformed and muscle physiology and motor behaviors were abnormal. In contrast, extrafusal myofiber phenotype, muscle physiology, and (except for muscle strength tests) motor behaviors were all normal after the rescue of MNs by genetic deletion of the proapoptotic gene Bax. However, there was an increase in intrafusal muscle fibers (spindles) in Bax knock-out versus both wild-type and MyoGDNF mice. Together, these data indicate that after the prevention of MN death, the neuromuscular system becomes transformed in novel ways to compensate for the presence of the thousands of excess cells.