Abstract
Injured nerve terminals of neuromuscular junctions (NMJs) can regenerate. This remarkable and complex response is governed by molecular signals that are exchanged among the cellular components of this synapse: motor axon nerve terminal (MAT), perisynaptic Schwann cells (PSCs), and muscle fiber. The nature of signals that govern MAT regeneration is ill-known. In the present study the spider toxin α-latrotoxin has been used as tool to investigate the mechanisms underlying peripheral neuroregeneration. Indeed this neurotoxin induces an acute, specific, localized and fully reversible damage of the presynaptic nerve terminal, and its action mimics the cascade of events that leads to nerve terminal degeneration in injured patients and in many neurodegenerative conditions. Here we provide evidence of an early release by degenerating neurons of adenosine triphosphate as alarm messenger, that contributes to the activation of a series of intracellular pathways within Schwann cells that are crucial for nerve regeneration: Ca2+, cAMP, ERK1/2, and CREB. These results contribute to define the cross-talk taking place among degenerating nerve terminals and PSCs, involved in the functional recovery of the NMJ.
Highlights
The neuromuscular junction (NMJ) is the specialized anatomical structure where the electric signal traveling along the axon is converted into a chemical message, which binds to post-synaptic receptors causing muscle contraction
motor axon terminal (MAT) is covered by a multi-cellular carpet of perisynaptic Schwann cells (PSCs), and MAT–PSCs are enveloped by the permeable basal lamina (BL) separating axon terminal from muscle fiber (MF)
When cerebellar granular neurons (CGNs) in co-cultures with SCs are exposed to α-Ltx, bulges or varicosities appear along neurites within few minutes, and intracellular calcium levels progressively rise within these characteristic rounded structures, hallmarks of intoxication, and along neurites (Bonanomi et al, 2005; Tedesco et al, 2009)
Summary
The neuromuscular junction (NMJ) is the specialized anatomical structure where the electric signal traveling along the axon is converted into a chemical message, which binds to post-synaptic receptors causing muscle contraction. This synapse consists of three main components: motor axon terminal (MAT), muscle fiber (MF), and perisynaptic Schwann cells (PSCs). Neuromuscular junctions are often exposed to mechanical traumas and represent the main target of several chemicals and biologic toxins During evolution, both animals and bacteria have developed toxins which selectively interfere with nerve–muscle transmission, causing a neuroparalysis which frequently leads to death (Schiavo et al, 2000). In many neuromuscular diseases such as amyotrophic lateral sclerosis and immune-mediated disorders, including the Guillain–Barré and Miller Fisher syndromes, the synaptic transmission between motor neurons (MNs) and muscle cells is compromised, with demyelination and axonal degeneration (Yuki and Hartung, 2012; Moloney et al, 2014)
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