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

Cells. 2020 Jan 21;9(2):260. doi: 10.3390/cells9020260.


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.

Keywords: ADAMTS 4/5; D1/D5 receptors; NMDA receptors; brevican; chondroitin sulfate proteoglycan.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAMTS Proteins / metabolism
  • Animals
  • Brevican / metabolism
  • Calcium Channels, L-Type / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Extracellular Matrix / metabolism*
  • Furin / metabolism
  • Homer Scaffolding Proteins / metabolism
  • Ion Channel Gating
  • Male
  • Prefrontal Cortex / metabolism
  • Presynaptic Terminals / metabolism*
  • Rats, Wistar
  • Receptors, Dopamine / metabolism*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synapses / metabolism*


  • Bcan protein, rat
  • Brevican
  • Calcium Channels, L-Type
  • Homer Scaffolding Proteins
  • Homer1 protein, rat
  • Receptors, Dopamine
  • Receptors, N-Methyl-D-Aspartate
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Furin
  • ADAMTS Proteins