Dopamine-Induced Changes in G alpha(olf) Protein Levels in Striatonigral and Striatopallidal Medium Spiny Neurons Underlie the Genesis of L-DOPA-Induced Dyskinesia in Parkinsonian Mice

作者：Morigaki Ryoma; Okita Shinya; Goto Satoshi^*

来源：Frontiers in Cellular Neuroscience, 2017, 11: 26.

DOI：10.3389/fncel.2017.00026

• olfactory type G-protein alpha subunit
• dopamine
• striatum
• Parkinson's disease
• L-DOPA-induced dyskinesia

The dopamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), exerts powerful therapeutic effects but eventually generates L-DOPA-induced dyskinesia (LID) in patients with Parkinson's disease (PD). LID has a close link with deregulation of striatal dopamine/cAMP signaling, which is integrated by medium spiny neurons (MSNs). Olfactory type G-protein a subunit (G alpha(olf)), a stimulatory GTP-binding protein encoded by the GNAL gene, is highly concentrated in the striatum, where it positively couples with dopamine D-1 (D1R) receptor and adenosine A(2A) receptor (A(2A)R) to increase intracellular cAMP levels in MSNs. In the striatum, D(1)Rs are mainly expressed in the MSNs that form the striatonigral pathway, while D(2)Rs and A(2A)Rs are expressed in the MSNs that form the striatopallidal pathway. Here, we examined the association between striatal G alpha(olf) protein levels and the development of LID. We used a hemi-parkinsonian mouse model with nigrostriatal lesions induced by 6-hydroxydopamine (6-OHDA). Using quantitative immunohistochemistry (IHC) and a dual-antigen recognition in situ proximity ligation assay (PLA), we here found that in the dopamine-depleted striatum, there appeared increased and decreased levels of G alpha(olf) protein in striatonigral and striatopallidal MSNs, respectively, after a daily pulsatile administration of L-DOPA. This leads to increased responsiveness to dopamine stimulation in both striatonigral and striatopallidal MSNs. Because G alpha(olf) protein levels serve as a determinant of cAMP signal-dependent activity in striatal MSNs, we suggest that L-DOPA-induced changes in striatal G alpha(olf) levels in the dopamine-depleted striatum could be a key event in generating LID.

• 出版日期2017-2-10