Title

 

Authors

F. Gardoni¹, C. Vastagh¹, V. Bagetta², J. Stanic¹, E. Zianni¹, B. Picconi², P. Calabresi³, M. Di Luca^1
 
1Department Pharmacological Sciences, University of Milano, Via Balzaretti 9, 20133 Milano;
²Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, 00143, Rome, Italy; 
³Clinica Neurologica, Università di Perugia, Ospedale S. Maria della Misericordia, 06156, Perugia, Italy.

 

Abstract

Molecular and functional interactions between glutamate and dopamine (DA) receptors regulate a large variety of brain functions and, when abnormal, they may contribute to and underlie numerous central nervous system (CNS) diseases. Here we show that D1 receptor activation at corticostriatal level induces a molecular and functional modification of the glutamatergic synapse. Treatment with D1 receptor agonist SKF38393 leads to a significant reduction of NR2A versus NR2B-containing NMDA receptors at synaptic sites and to a concomitant increase of GluR1-containing AMPA receptors insertion in the postsynaptic membrane. In addition, in vivo treatment with D1 receptor agonist induces a significant increase of dendritic spine head width of striatal medium spiny neurons. Notably, treatment of corticostriatal slices with NR2A antagonist NVP-AAM077 or with TAT2A (a cell-permeable peptide able to reduce NR2A-containing NMDA receptors) was sufficient to induce a similar significant morphological modification of dendritic spine head width. Conversely, NR2B antagonist ifenprodil blocked any morphological effect induced by D1 activation. Overall, we show that, in striatal spiny neurons, dopamine D1 receptor activation leads to a molecular, functional and morphological re-arrangement of the glutamatergic striatal synapse correlated to NR2A/NR2B subunits ratio in the postsynaptic compartment.