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

Abstract

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 corticostriatal synapses, and conclude that the extracellular signaling domain and its regulation by matrix metalloproteinases is critical for developing and expressing drug seeking behaviors.

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…The integrins and the intracellular CAMs are the most well studied CAMs in the brain (Wiggins et al, 2011;Niedringhaus et al, 2012;Lonskaya et al, 2013). Because the ECM can respond to activity in the other three compartments of the tripartite synapse, it is now considered a fourth synaptic compartment, causing the emergence of the term tetrapartite synapse (for review, see Smith et al, 2015a). For example, activity-dependent ECM signaling can liberate latent growth factors (Saygili et al, 2011), affect synaptic and extrasynaptic receptor content (Michaluk et al, 2009), and stimulate morphologic and physiologic synaptic plasticity .…”

A Glitch in the Matrix: Aberrant Extracellular Matrix Proteolysis Contributes to Alcohol Seeking

“…MMPs are Zn 2+ -dependent proteolytic enzymes that are primary regulators of the composition and integrity of the extracellular matrix. Dysregulation of MMP-9 activity has been reported following chronic use of alcohol, nicotine, opiates, cocaine, and methamphetamine (1). A family of 23 extracellular matrix–remodeling MMPs were originally described for their roles in angiogenesis, tumor cell invasion, and wound healing, and were thought to function primarily in regulating structural support surrounding cells (2).…”

Involvement of the cerebellum in cocaine-induced memory

“…Addiction can be described as a pathological form of learning in which overconsolidated drug-associated memories promote drug seeking responses, even after decades of 28 abstinence (Smith et al, 2015). Importantly, PNN have become one of the more promising targets for drug-related neuroplasticity modifications (Blacktop et al, 2017).…”

“…Matrix metalloproteases (MMPs) are enzymes that degrade the ECMs as well as other molecules expressed on the cell surface. The most studied MMPs in the central nervous system are MMP-2, MMP-3 and MMP-9 (Smith et al, 2015). Besides, an exogenous way to disrupt the PNNs is the use of Chondroitinase-ABC (ChABC).…”

“…El estudio de los PNNs ha ganado relevancia en los últimos años como mecanismo de plasticidad fundamental cuando surgió una nueva construcción conceptual denominada "la sinapsis tetrapartita" (Dityatev y Rusakov, 2011;Smith et al, 2015). Más allá del punto de vista tradicional sobre la función sináptica, este concepto emergente incluyó dos nuevos elementos en la arquitectura sináptica junto con los clásicos elementos presinápticos y postsinápticos: astrocitos y MEC.…”