Review
Extrasynaptic therapeutic targets in substance use and stress disorders

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Highlights

  • Animal models of substance use and stress disorders arise from overlapping enduring changes in synaptic plasticity produced by drug use or stress exposure.

  • Non-neuronal components of the synapse, including astroglia and the extracellular matrix establish and sustain maladaptive synaptic plasticity.

  • Synaptic proximity of astroglial processes is altered by environmental stress and addictive drug use, conferring relapse-vulnerability.

  • Catalytic signaling in the extracellular matrix is necessary for conditioned drug seeking and stress responding.

  • Regulating astroglial plasticity and extracellular matrix signaling highlights novel molecular targets for treating addictive drug use and stress disorders.

Treatments for substance use and stress disorders are based on ameliorating behavioral symptoms, not on reversing the synaptic pathology that has the potential to cure disorders. This failing arises in part from a research focus on how pre- and postsynaptic physiology is changed even though key neuropathology exists in the perisynaptic neuropil that homeostatically regulates synaptic transmission. We explore recent findings from the substance use and stress disorder literature pointing to a key role for perisynaptic astroglia and signaling in the extracellular matrix (ECM) in regulating synaptic pathology. We conclude that drugs and stress initiate long-lasting changes in brain synapses via enduring neuroadaptations in astroglia and the ECM, and that modulating extrasynaptic regulators may be therapeutically useful.

Section snippets

Targeting synaptic plasticity to cure psychiatric disorders

Our current capacity to cure psychiatric disorders depends on psychosocial interventions to induce the brain plasticity (see Glossary) that changes maladaptive behavior. Pharmacological and physiological interventions are useful for controlling various behavioral symptoms but are largely ineffective in reversing neuropathology and curing psychiatric disorders, including substance use disorders (SUDs) and post-traumatic stress disorder (PTSD). For SUDs and PTSD, reliance on psychosocial

Tetrapartite synapses and non-neuronal contributions to synaptic plasticity

Synaptic plasticity is most often quantified as experience-induced changes in presynaptic transmitter release and/or in the strength of postsynaptic responses to released transmitter. Some of these measures can now be made in behaving animals due to advances in invasive brain recording, imaging, and in reagents that allow visualizing released transmitter and dendritic spine morphology over the course of seconds and minutes [4]. Through this research, we can be confident that pre- and

Astroglial plasticity induced by addictive drugs and stress

Astrocytes perform a host of support roles in the brain contributing to neuronal function, neuroinflammatory responses, and blood flow recruitment [19., 20., 21.]. Astroglia have a ramified structure providing contiguity to many thousands of synapses, brain capillaries, and other astroglia. Thus, astrocytes are morphologically positioned to homeostatically coordinate function across many elements in the neuropil, including synapses. Coordinating multiple synapses is accomplished in part through

ECM proteins regulate synapse stability and plasticity

The ECM is a macromolecular network surrounding all cells in the brain that serves as a scaffold connecting glia and neurons via cell adhesion molecules and is composed of proteoglycans and glycoproteins that are synthesized and secreted into the extracellular space by glia and neurons [52]. The ECM is not a homogeneous network and exists in at least two distinct forms: diffuse and condensed. The condensed form, called perineuronal nets (PNNs), surrounds primarily the soma and proximal

Astroglia and ECM signaling and novel drug targets for treating SUDs or PTSD

Figure 1 reveals several molecular targets in tetrapartite synaptic signaling that can ameliorate or promote drug seeking in animal models of relapse. These potential targets and their impact on drug-induced tetrapartite synaptic changes and cue-induced drug seeking and/or stress responding are summarized in Table 1. Modulating many of the signaling loci in tetrapartite physiology outlined in Figure 1 by drugs or brain stimulation prevents cue-induced drug, but not sucrose seeking in animal

Concluding remarks and future perspectives

Synaptic plasticity is regulated by a homeostatic balance of physiological activity in four morphological synaptic compartments: the canonical pre- and postsynapse, perisynaptic astroglial processes, and the ECM. All four compartments can undergo enduring plasticity in response to strong environmental stimuli. Here we show that addictive drug use or stressful experiences alter the homeostatic relationships between compartments. The altered balance between synaptic compartments endures for weeks

Acknowledgments

The authors are grateful for funding for some of the research described in this manuscript, including United States Public Health Service (USPHS) grants to DA044782 (A.K.), DA012513 (P.W.K.), DA016511 (P.W.K.), DA046373 (P.W.K.), and a merit award from the Veteran’s Administration BX004727 (P.W.K.).

Declaration of interests

No interests are declared.

Glossary

Arg-Gly-Asp (RGD) domain
this domain is contained on some extracellular matrix proteins and constitutes the minimal recognition sequence for integrin binding.
β3-integrin
a subunit of integrin that plays an important role in synaptic plasticity and is activated by catalytic signaling in the extracellular matrix.
Brain plasticity
morphological and physiological changes in brain structure and function.
D1 and D2 receptors expressing medium spiny neurons (D1- and D2-MSNs)
these two neural subtypes

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