Functional adaptation of glial cells at neuromuscular junctions in response to injury.

Synaptic elements from neuromuscular junctions (NMJs) undergo massive morphological and functional changes upon nerve injury. While morphological changes of NMJ-associated glia in response to injury has been investigated, their functional properties remain elusive. Perisynaptic Schwann cells (PSCs), glial cells at the NMJ, are essential for NMJ maintenance and repair, and are involved in synaptic efficacy and plasticity. Importantly, these functions are regulated by PSCs ability to detect synaptic transmission through, notably, muscarinic (mAChRs) and purinergic receptors' activation. Using Ca2+ imaging and electrophysiological recordings of synaptic transmission at the mouse NMJ, we investigated PSC receptors activation following denervation and during reinnervation in adults and at denervated NMJs in an ALS mouse model (SOD1G37R ). We observed reduced PSCs mAChR-mediated Ca2+ responses at denervated and reinnervating NMJs. Importantly, PSC phenotypes during denervation and reinnervation were distinct than the one observed during NMJ maturation. At denervated NMJs, exogenous activation of mAChRs greatly diminished galectin-3 expression, a glial marker of phagocytosis. PSCs Ca2+ responses at reinnervating NMJs did not correlate with the number of innervating axons or process extensions. Interestingly, we observed an extended period of reduced PSC mAChRs activation after the injury (up to 60 days), suggesting a glial memory of injury. PSCs associated with denervated NMJs in an ALS model (SOD1G37R mice) did not show any muscarinic adaptation, a phenotype incompatible with NMJ repair. Understanding functional mechanisms that underlie this glial response to injury may contribute to favor complete NMJ and motor recovery.

Calcium signaling in Schwann cells at synaptic and extra-synaptic sites: active glial modulation of neuronal activity.

Glial cells are widely dispersed in the central nervous system (CNS) as well as in the peripheral nervous system (PNS). In the PNS, perisynaptic Schwann cells (PSCs) are the glial cells associated with the pre- and postsynaptic elements of the neuromuscular junction (NMJ). They, as other glial cells of the CNS, respond to high-frequency motor nerve stimulation with an increase in intracellular Ca(2+). In addition to detecting and responding to neurotransmission, PSCs are involved in short-term plasticity events where they depress neurotransmission through G-protein-dependent mechanisms and potentiate synaptic activity via Ca(2+)-dependent mechanisms. In this review, we will discuss evidence that outlines the role of PSCs in short- and long-term modulation of synaptic activity. We will also emphasize present functional similarities and differences in PSC activation at different NMJs. The importance of glial-neural interactions along myelinating axons will also be discussed.

Modulation of neurotransmission by reciprocal synapse-glial interactions at the neuromuscular junction.

Perisynaptic Schwann cells are glial cells that are closely associated with pre- and postsynaptic elements of the neuromuscular junction. Recent evidence shows that these cells detect and modulate neurotransmission in an activity-dependent fashion. Through G-protein signalling and Ca(2+) released from internal stores they can decrease or increase neurotransmitter release, respectively. Thus, they help to establish the level of neurotransmission associated with activity dependent short-term synaptic plasticity. We discuss evidence implicating perisynaptic Schwann cells as being active partners in neurotransmission at the neuromuscular junction, with emphasis on the modulation of short-term plasticity and potential implications for long-term changes.