Abstract:
:The GluN2 subunits that compose N-methyl-d-aspartate receptors (NMDARs) are attractive drug targets for therapeutic intervention in several diseases, in particular Parkinson's disease (PD). The precise roles and possible dysfunctions of NMDARs attributed to specific GluN2 subunits are however unresolved. Through the use of CIQ, a novel positive allosteric modulator of GluN2C/GluN2D-containing NMDARs, we have examined the functions and dysfunctions of NMDARs made of GluN2D in the striatum of control mice and of the 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. We found that CIQ (20μM), applied to corticostriatal brain slices, increased the firing rate of spontaneously active cholinergic interneurons in the striatum of control mice and in the intact striatum of 6-OHDA-lesioned mice. CIQ also presynaptically depressed GABAergic neurotransmission through a cholinergic mechanism, but had no effect on glutamatergic neurotransmission, in medium spiny projection neurons (MSNs) of control and intact striatum. In the dopamine-depleted striatum, the effect of CIQ on the firing of cholinergic interneurons and GABAergic neurotransmission was lost. However, CIQ increased glutamatergic neurotransmission in MSNs. We also found that the protein levels of GluN2D were increased in the dopamine-depleted striatum as compared to the intact striatum. However, the contribution of GluN2D-containing NMDARs to whole-cell NMDA currents was reduced in cholinergic interneurons and increased in MSNs. These results demonstrate an impaired modulatory role of GluN2D-containing NMDARs on the activity of cholinergic interneurons and inhibitory transmission in the dopamine-depleted striatum. However, potentiation of excitatory neurotransmission occurs upon activation of these receptors. Thus, altered functions of GluN2D-containing NMDARs might contribute to adaptive changes in experimental Parkinsonism.
journal_name
Exp Neuroljournal_title
Experimental neurologyauthors
Feng ZJ,Zhang X,Chergui Kdoi
10.1016/j.expneurol.2014.03.001subject
Has Abstractpub_date
2014-05-01 00:00:00pages
154-60eissn
0014-4886issn
1090-2430pii
S0014-4886(14)00078-8journal_volume
255pub_type
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