Nonneuronal contributions to synaptic function

Synapses are elegantly integrated signaling hubs containing the canonical synaptic elements, neuronal pre- and postsynapses, along with other components of the neuropil, including perisynaptic astroglia and extracellular matrix proteins, as well as microglia and oligodendrocytes. Signaling within these multipartite hubs is essential for synaptic function and is often disrupted in neuropsychiatric disorders. We review data that have refined our understanding of how environmental stimuli shape signaling and synaptic plasticity within synapses. We propose working models that integrate what is known about how different cell types within the perisynaptic neuropil regulate synaptic functions and dysfunctions that are elicited by addictive drugs. While these working models integrate existing findings, they are constrained by a need for new technology. Accordingly, we propose directions for improving reagents and experimental approaches to better probe how signaling between cell types within perisynaptic ecosystems creates the synaptic plasticity necessary to establish and maintain adaptive and maladaptive behaviors.