ABSTRACT
Title
Role of striatal spiny neurons and cholinergic interneurons in the D2/A2A receptor interaction: implication for Parkinson’s disease
Authors
A. Tozzi1,2, A. de Iure 1,2, M. Di Filippo 1,2, M. Tantucci 1, C. Costa 1, F. Borsini 3, C. Giampà 2, F.R. Fusco 2, P. Calabresi 1,2
1Clinica Neurologica, University of Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy
2 Fondazione Santa Lucia - IRCCS, Rome, Italy
3 Sigma-tau Industrie Riunite, Pomezia, Italy
1Clinica Neurologica, University of Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy
2 Fondazione Santa Lucia - IRCCS, Rome, Italy
3 Sigma-tau Industrie Riunite, Pomezia, Italy
Abstract
A functional antagonism exists between A2A adenosine and D2 dopamine (DA) receptors that are co-expressed in striatal medium spiny neurons (MSNs) of the indirect pathway and A2A receptor antagonists are currently under investigation as putative agents for Parkinson’s disease (PD) treatment. Since A2A-D2 receptor interaction could also occur in other neuronal subtypes, we have studied this relationship in MSNs of the direct and indirect pathways as well as in striatal cholinergic interneurons.
We have performed electrophysiological measurement by means of sharp electrodes and patch-clamp recordings in physiological conditions and we found that endogenous cannabinoids (eCBs) play a pivotal role in the inhibitory effect on striatal glutamatergic transmission produced by the activation of D2 DA receptors and blockade of A2A receptors in D2- and D1-expressing striatal MSNs. In experimental models of PD the inhibition of striatal glutamatergic activity exerted by D2 receptor activation did not require the concomitant inhibition of A2A receptors while it was still dependent on the activation of CB1 receptors in both D2- and D1-expressing MSNs.
In cholinergic interneurons we found co-expression of D2 and A2A receptors and a reduction of the firing frequency exerted by the same drugs that reduced excitatory transmission in MSNs.
In cholinergic interneurons we found co-expression of D2 and A2A receptors and a reduction of the firing frequency exerted by the same drugs that reduced excitatory transmission in MSNs.
These evidence support the hypothesis that striatal cholinergic interneurons, virtually projecting to all MSN subtypes, are involved in the D2/A2A and eCB-mediated effects observed on both subpopulations of MSN in physiological condition and in experimental PD.
We have performed electrophysiological measurement by means of sharp electrodes and patch-clamp recordings in physiological conditions and we found that endogenous cannabinoids (eCBs) play a pivotal role in the inhibitory effect on striatal glutamatergic transmission produced by the activation of D2 DA receptors and blockade of A2A receptors in D2- and D1-expressing striatal MSNs. In experimental models of PD the inhibition of striatal glutamatergic activity exerted by D2 receptor activation did not require the concomitant inhibition of A2A receptors while it was still dependent on the activation of CB1 receptors in both D2- and D1-expressing MSNs.
In cholinergic interneurons we found co-expression of D2 and A2A receptors and a reduction of the firing frequency exerted by the same drugs that reduced excitatory transmission in MSNs.
In cholinergic interneurons we found co-expression of D2 and A2A receptors and a reduction of the firing frequency exerted by the same drugs that reduced excitatory transmission in MSNs.
These evidence support the hypothesis that striatal cholinergic interneurons, virtually projecting to all MSN subtypes, are involved in the D2/A2A and eCB-mediated effects observed on both subpopulations of MSN in physiological condition and in experimental PD.