ReviewThe tetrapartite synapse: Extracellular matrix remodeling contributes to corticoaccumbens plasticity underlying drug addiction

- The extracellular matrix forms a 4th synaptic compartment important for plasticity.
- The extracellular matrix is regulated by matrix metalloproteinases (MMPs).
- MMPs contribute to relapse-induced synaptic potentiation in the accumbens.

Synaptic plasticity has long been known to involve three key elements of neuropil, the presynapse, the postsynapse and adjacent glia. Here we review the role of the extracellular matrix in synaptic plasticity as a necessary component forming the tetrapartite synapse. We describe the role of matrix metalloproteinases as enzymes sculpting extracellular proteins and thereby creating an extracellular signaling domain required for synaptic plasticity. Specifically we focus on the role of the tetrapartite synapse in mediating the effects of addictive drugs at cortico-striatal synapses, and conclude that the extracellular signaling domain and its regulation by matrix metalloproteinases is critical for developing and expressing drug seeking behaviors.This article is part of a Special Issue entitled SI:Addiction circuits.