Dopamine Receptor Activation Modulates the Integrity of the Perisynaptic Extracellular Matrix at Excitatory Synapses.

Jessica Mitlöhner,Armand Blondiaux,Alexander Dityatev,Rahul Kaushik,Renato Frischknecht,Max F K Happel,Hartmut Niekisch,Christine E Gee,Constanze Seidenbecher,Eckart Gundelfinger

doi:10.3390/cells9020260

Abstract

In the brain, Hebbian-type and homeostatic forms of plasticity are affected by neuromodulators like dopamine (DA). Modifications of the perisynaptic extracellular matrix (ECM), which control the functions and mobility of synaptic receptors as well as the diffusion of transmitters and neuromodulators in the extracellular space, are crucial for the manifestation of plasticity. Mechanistic links between synaptic activation and ECM modifications are largely unknown. Here, we report that neuromodulation via D1-type DA receptors can induce targeted ECM proteolysis specifically at excitatory synapses of rat cortical neurons via proteases ADAMTS-4 and -5. We showed that receptor activation induces increased proteolysis of brevican (BC) and aggrecan, two major constituents of the adult ECM both in vivo and in vitro. ADAMTS immunoreactivity was detected near synapses, and shRNA-mediated knockdown reduced BC cleavage. We have outlined a molecular scenario of how synaptic activity and neuromodulation are linked to ECM rearrangements via increased cAMP levels, NMDA receptor activation, and intracellular calcium signaling.

Highlights

Synaptic transmission and plasticity are affected by perisynaptic and extrasynaptic factors including the extracellular matrix (ECM), glia-derived components, and neuromodulators
In addition to BC, we included ACAN in our investigations, since this lectican is present at perisynaptic sites [39] and is expressed in the cortex, where it has been shown to act as a gatekeeper for physiological plasticity [40]
In a very elegant study, Yagishita et al (2014) demonstrated that the DA-mediated support of spine enlargement upon stimulation has to occur within a narrow time window after NMDAR activation [64]. This mechanism of DA action involves D1 receptors (D1Rs), protein kinase A (PKA), NMDAR, and calmodulin-dependent kinase II (CaMKII), which is in good agreement with our findings presented here, suggesting the hypothesis that the D1Rs-induced ECM remodeling observed by us may be involved in catecholaminergic spine morphology regulation

Summary

Introduction

Synaptic transmission and plasticity are affected by perisynaptic and extrasynaptic factors including the extracellular matrix (ECM), glia-derived components, and neuromodulators. Cells 2020, 9, 260 comprises such diverse mechanisms as regulation of presynaptic neurotransmitter release, e.g., via control of axon terminal excitability or calcium influx, postsynaptic neurotransmitter detection via regulated receptor insertion, or synaptic integration in networks (summarized in Reference [1]). Dopaminergic signaling is mediated via five different G protein-coupled receptors which can be assigned to two major subgroups: D1-like and D2-like DA receptors [4,5,6]. Both receptor subgroups have been shown to be coupled to adenylyl cyclase (AC). D2 (D2R) and D3 receptors have been found to be expressed both postsynaptically on DA target cells and presynaptically on dopaminergic neurons [8,9]

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Conclusion