Perisynaptic Glia Discriminate Patterns of Motor Nerve Activity and Influence Plasticity at the Neuromuscular Junction

In the nervous system, the induction of plasticity is coded by patterns of synaptic activity. Glial cells are now recognized as dynamic partners in a wide variety of brain functions, including the induction and modulation of various forms of synaptic plasticity. However, it appears that glial cells are usually activated by stereotyped, sustained neuronal activity, and little attention has been given to more subtle changes in the patterns of synaptic activation. To this end, we used the mouse neuromuscular junction as a simple and useful model to study glial modulation of synaptic plasticity. We used two patterns of motor nerve stimulation that mimic endogenous motor-neuronal activity. A continuous stimulation induced a post-tetanic potentiation and a phasic Ca2+ response in perisynaptic Schwann cells (PSCs), glial cells at this synapse. A bursting pattern of activity induced a post-tetanic depression and oscillatory Ca2+ responses in PSCs. The different Ca2+ responses in PSCs indicate that they decode the pattern of synaptic activity. Furthermore, the chelation of glial Ca2+ impaired the production of the sustained plasticity events indicating that PSCs govern the outcome of synaptic plasticity. The mechanisms involved were studied using direct photo-activation of PSCs with caged Ca2+ that mimicked endogenous plasticity. Using specific pharmacology and transgenic knock-out animals for adenosine receptors, we showed that the sustained depression was mediated by A1 receptors while the sustained potentiation is mediated by A(2A) receptors. These results demonstrate that glial cells decode the pattern of synaptic activity and subsequently provide bidirectional feedback to synapses.