ABSTRACT
Dopamine (DA) is a potent neuromodulator known to influence glutamatergic transmission in striatal medium spiny neurons (MSNs). It acts on D1- and D2-like DA receptors that are expressed on two distinct subpopulations. MSNs projecting to the substantia nigra express D1 receptors (D1Rs), while those projecting to the lateral globus pallidus express D2 receptors (D2Rs). D1R signalling in particular can increase excitatory transmission through varied protein kinase A-dependent, cell-autonomous pathways. Mechanisms by which D1R signalling could increase excitatory transmission in D2R-bearing MSNs have been relatively less explored. Herein, the possibility is considered that D1R agonists increase levels of soluble factors that subsequently influence N-methyl-D-aspartate (NMDA)-stimulated calcium flux in D2R neurons. This study focuses on matrix metalloproteinases (MMPs) and MMP-generated integrin binding ligands, important soluble effectors of glutamatergic transmission that may be elevated in the setting of excess DA. It was observed that DA and a D1R agonist, SKF81297, increase MMP activity in extracts from striatal slices, as determined by cleavage of the substrate ß-dystroglycan. Using mice engineered to express the calcium indicator GCaMP3 in striatopallidal D2R-bearing neurons, it was also observed that SKF81297 pretreatment of slices (60 min) potentiates NMDA-stimulated calcium increases in this subpopulation. Effects are diminished by pretreatment with an antagonist of MMP activity or an inhibitor of integrin-dependent signalling. Together, results suggest that DA signalling can increase excitatory transmission in D2R neurons through an MMP-dependent mechanism. Future studies may be warranted to determine whether D1R-stimulated MMP-dependent processes contribute to behaviours in which increased activity in striatopallidal MSNs plays a role.
