The neuromuscular synapse, like synapses in the central nervous system, is now believed to have not two, but three essential cellular components: the presynaptic motoneuron, the postsynaptic muscle fiber, and the perisynaptic terminal Schwann cell (a type of neuroglia). Interactions among these three cell types change as the animal matures, and a major goal of my research is to elucidate these developmental changes and the mechanisms that underlie them. Understanding interactions among the three cell types that comprise the synapse is essential for understanding synapse formation and synaptic plasticity -- important in development, in learning and memory, after injury, and during disease processes and natural aging.
The neuromuscular junction has proven to be an extremely useful model system and offers several advantages, including easy access for manipulations of presynaptic, postsynaptic, or perisynaptic cells. Individual neuromuscular synapses can also be imaged repeatedly in the living animal to observe synaptic changes both during normal development and after experimental manipulations. I participated in a collaborative effort to generate transgenic mice in which Schwann cells express enhanced green fluorescent protein (GFP) under the control of the S100 promoter. This allows us to better visualize Schwann cells in living animals, enabling for the first time a variety of studies of the behavior of Schwann cells in vivo.
 |
|
|
|
 |
|
||
 |
 |
 |
|
 |
|
||
 |
|
||
 |
|
||
 |
|
||
 |
|
||
 |
|
||
 |
|
||
 |
|
||
 |
|
||
 |
|
||
 |
|
||
 |
|
||
 |
|
||
One area of research in the lab focuses on the plastic response of neuromuscular systems
to partial denervation of a muscle and the possible role of Schwann cells. In adulthood, mammalian motoneurons show excellent compensation for the
loss of neighboring motoneurons. After partial denervation of an adult muscle, the remaining motoneurons extend sprouts that reinnervate denervated
fibers. In contrast, after partial denervation of a muscle in early postnatal life, the remaining motoneurons fail to reinnervate denervated muscle
fibers. One objective of the research in my lab is to understand and explain these developmental differences in the neuronal response to injury.
Interestingly, Schwann cells also show a developmental change in response to nerve injury -- they extend processes after nerve injury in adult animals,
but undergo massive cell death after nerve injury in neonatal animals.
Experimental partial denervation mimics one of the effects of injury or certain disease processes. We are interested in extending our observations
to animal models of neuromuscular disease [e.g., amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA)]. Studies suggest that terminal
Schwann cells play an important role in determining the response of motoneurons to the challenge of partial denervation, but little work has focused
on the behavior and possible role of terminal Schwann cells in neurodegenerative diseases that target neuromuscular systems.
A third and relatively new area of research in the lab focuses on the response of neuromuscular systems to the challenges of aging. In many ways,
the aging neuromuscular junction behaves similarly to the developing neuromuscular junction, although the underlying mechanisms may differ. We have
begun studies on age-related changes at the neuromuscular junction, with a particular focus on the terminal Schwann cells.
Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, Xing Y, Lubischer
JL, Krieg PA, Krupenko SA, Thompson WJ, Barres BA. (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: A new resource
for understanding brain development and function. Journal
of Neuroscience 28(1):264-278.
Malomouzh AI, Nikolsky EE, Lieberman EM, Sherman JA, Lubischer JL, Grossfeld RM, Urazaev AKh. (2005) Effect of N-acetylaspartylglutamate (NAAG)
on non-quantal release of acetylcholine at the neuromuscular synapse of rats.
Journal of Neurochemistry 94:257-267.
Lubischer JL, Unguez GA, Pierotti DJ, Roy RR, Edgerton VR (2005) Reinnervation of the rat levator ani muscle after neonatal denervation. Journal
of Neurobiology 63(3):188-198.
Zuo Y, Lubischer JL, Kang H, Tian L, Mikesh M, Marks A, Scofield VL, Maika S, Newman C, Krieg P, Thompson W. (2004) Fluorescent proteins driven
in mice by the S100B promoter give variegated labeling of glia, neurons, macrophages, and dendritic cells of the immune system. Journal
of Neuroscience 24(49):10999-11009.
Lubischer JL, Bebinger DM (1999) Regulation of terminal Schwann cell number at the adult neuromuscular junction. Journal
of Neuroscience 19(24):46RC.
Lubischer JL, Thompson WJ (1999) Neonatal partial denervation results in nodal, but not terminal, sprouting and a decrease in efficacy of remaining neuromuscular junctions in rat soleus muscle. Journal of Neuroscience 19(20):8931-8944.
Lubischer JL, Thompson WJ (1998) A neuregulin, glial growth factor (GGF2), reduces SNB motoneuron death during normal development. Society for Neuroscience Abstracts 24:1790.
Lubischer JL, Arnold AP (1995) Evidence for target regulation of the development of androgen sensitivity in rat spinal motoneurons. Developmental Neuroscience 17:106-117.
Lubischer JL, Arnold AP (1995) Axotomy of developing rat spinal motoneurons: cell survival, soma size, muscle recovery, and the influence of testosterone. Journal of Neurobiology 26:225-240.
