Evidence showing the ability of glial cells to detect, respond to and modulate synaptic transmission and plasticity has contributed to the notion of glial cells as active synaptic partners. However, synaptically induced plasticity of glia themselves remains ill defined. Here we used the amphibian neuromuscular junction (NMJ) to study plasticity of perisynaptic Schwann cells (PSCs), glial cells at this synapse, following long-term in vivo modifications of synaptic activity. We used two models that altered synaptic activity in different manners. First, chronic blockade of postsynaptic nicotinic receptors using α-bungarotoxin (α-BTx) decreased facilitation, increased synaptic depression and decreased post-tetanic potentiation (PTP). Second, chronic nerve stimulation increased facilitation and resistance to synaptic depression, while leaving PTP unaltered. Our results indicate that there is no direct relationship between transmitter release and PSC calcium responses. Indeed, despite changes in transmitter release and plasticity in stimulated NMJs, nerve-evoked PSC calcium responses were similar to control. Similarly, PSC calcium responses in α-BTx treated NMJs were delayed and smaller in amplitude, even though basal level of transmitter release was increased. Also, when isolating purinergic and muscarinic components of PSC calcium responses, we found an increased sensitivity to ATP and a decreased sensitivity to muscarine in chronically stimulated NMJs. Conversely, in α-BTx treated NMJs, PSC sensitivity remained unaffected, but ATP-and muscarine-induced calcium responses were prolonged. Thus, our results reveal complex modifications of PSC properties, with differential modulation of signalling pathways that might underlie receptor regulation or changes in Ca 2+ handling. Importantly, similar to neurons, perisynaptic glial cells undergo plastic changes induced by altered synaptic activity. IntroductionThere is now a growing body of evidence indicating that glial cells play an active role in synaptic communication throughout the nervous system. They are indeed involved in the regulation of synaptic transmission and plasticity (reviewed by Auld & Robitaille, 2003;Halassa et al. 2007), believed to be the functional basis of learning and memory. Hence, glial cells are full participants at synapses and contribute actively to neuronal processing and integration. Complementary to their active role in regulating synaptic plasticity, glial cells themselves exhibit activity-dependent changes in their properties during development (Pasti et al. 1997). However, there is no direct evidence that glial cell modifications are specific and adapted to the level of synaptic activity and that they can occur in mature systems. Such adaptation, concomitant with pre-and postsynaptic plasticity, would be essential to maintain appropriate communication between all components of the tripartite synapse. Hence, the goal of this work was to test whether the properties and activation of perisynaptic glial cells are differentially regulated in re...

Prolonged changes in motor neurone activity can result in long-term changes in synaptic transmission. We investigated whether mechanisms commonly thought to be involved in determining synaptic efficacy of vertebrate motor neurones are involved in these long-term changes. The nerve supplying the cutaneus pectoris muscle was chronically stimulated via skin surface electrodes in freely moving frogs for 5-7 days. Chronic stimulation induced a 50% reduction in evoked endplate potential (EPP) amplitude at stimulated neuromuscular junctions (NMJs). These changes appear to be presynaptic since miniature EPP (mEPP) amplitude was unchanged while mEPP frequency was decreased by 46% and paired-pulse facilitation was increased by 26%. High frequency facilitation (40 Hz, 2 s) was also increased by 89%. Moreover, stimulated NMJs presented a 92% decrease in synaptic depression (40 Hz, 2 s). An increase in mitochondrial metabolism was observed as indicated by a more pronounced labelling of active mitochondria (Mitotracker) in stimulated nerve terminals, which could account for their greater resistance to synaptic depression. NMJ length visualized by α-bungarotoxin staining of nAChRs was not affected. Presynaptic calcium signals measured with Calcium Green-1 were larger in stimulated NMJs at low frequency (0.2 Hz) and not different from control NMJs at higher frequency (40 Hz, 2 s and 30 s). These results suggest that some mechanisms downstream of calcium entry are responsible for the determination of synaptic output, such as a down-regulation of some calcium-binding proteins, which could explain the observed results. The possibility of a change in frequenin expression, a calcium-binding protein that is more prominently expressed in phasic synapses, was, however, refuted by our results.

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.

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