GluN2D-containing NMDA receptors inhibit neurotransmission in the mouse striatum through a cholinergic mechanism: implication for Parkinson's disease
Article first published online: 11 FEB 2014
© 2014 International Society for Neurochemistry
Journal of Neurochemistry
Volume 129, Issue 4, pages 581–590, May 2014
How to Cite
J. Neurochem. (2014) 129, 581–590.
- Issue published online: 23 APR 2014
- Article first published online: 11 FEB 2014
- Accepted manuscript online: 29 JAN 2014 12:14PM EST
- Manuscript Accepted: 9 JAN 2014
- Manuscript Revised: 19 DEC 2013
- Manuscript Received: 18 OCT 2013
- Swedish Research Council. Grant Numbers: 2008-2636, 2011-2770
- Loo and Hans Ostermans Foundation for Geriatric Research
- Stiftelse Lars Hiertas Minne
- Swedish Society for Medical Research
- NMDA receptor;
- Parkinson's disease
The GluN2 subunits that compose NMDA receptors (NMDARs) determine functional and pharmacological properties of the receptor. In the striatum, functions and potential dysfunctions of NMDARs attributed to specific GluN2 subunits have not been clearly elucidated, although NMDARs play critical roles in the interactions between glutamate and dopamine. Through the use of amperometry and field potential recordings in mouse brain slices, we found that NMDARs that contain the GluN2D subunit contribute to NMDA-induced inhibition of evoked dopamine release and of glutamatergic neurotransmission in the striatum of control mice. Inhibition is likely mediated through increased firing in cholinergic interneurons, which were shown to express GluN2D. Indeed, NMDA-induced inhibition of both dopamine release and glutamatergic neurotransmission is reduced in the presence of muscarinic receptor antagonists and is mimicked by a muscarinic receptor agonist. We have also examined whether this function of GluN2D-containing NMDARs is altered in a mouse model of Parkinson's disease. We found that the inhibitory role of GluN2D-containing NMDARs on glutamatergic neurotransmission is impaired in the 6-hydroxydopamine lesioned striatum. These results identify a role for GluN2D-containing NMDARs and adaptive changes in experimental Parkinsonism. GluN2D might constitute an attractive target for the development of novel pharmacological tools for therapeutic intervention in Parkinson's disease.
We have examined the role of NMDA receptors composed of the GluN2D subunit in the mouse striatum. These receptors inhibit the release of dopamine and of glutamate through a mechanism that involves activation of cholinergic interneurons. This inhibitory role is impaired in the dopamine-depleted striatum. This study identifies GluN2D as a potential target for therapeutic intervention in Parkinson's disease.