| Objective:Dyskinesia is a severe drug complication after levodopa treatment of Parkinson's disease.Some studies have shown that the occurrence of dyskinesia may be related to dendritic remodeling and synaptic plasticity.The former mainly observed the morphology of dendritic spines,while the latter explained the problem from the electrophysiological point of view.The purpose of this study was to investigate whether the structural synaptic plasticity of dyskinesia occurs in D1 direct pathway by focusing on the morphological changes of dendritic spines in medium spiny neurons(MSNs)in dosal striatum and excitatory postsynaptic currents(EPSCs)were used to observe the plasticity of MSNs synaptic function in striatum.And whether eltoprazine,a 5-HT1A/B agonist,can alleviate dyskinesia through the above pathway,and observe whether pERK is associated with it.Methods:(1)The model of dyskinesia was induced by levodopa in mice with 6-OHDA hemiparkinsonism.The abnormal involuntary motor score(AIMs)was performed in the dyskinesia and eltoprazine treatment group to see if eltoprazine could improve the dyskinesia;(2)Microinjection of Lucifer Yellow dye into dorsolateral striatum and(3)stereotactic injection of rAAV-D1-mCherry-WPRE-pA,were used to observe the morphological changes of dendritic spines.Including the density and the density of different types of spines,to explore whether dyskinesia plays a role through D1 MSNs,and whether eltoprazine improves dyskinesia through D1 MSNs;(4)the changes of excitatory postsynaptic currents in each group were observed by patch clamp system.(5)To observe the changes of pERK in each group by western-blotting.Results:(1)the AIMs of dyskinesia group was different from that of eltoprazine group on the first day,and there was a difference among 20?40 and 60 minutes in the score of 180 minutes on the 14th day;(2)the results of intracellular microinjection of Lucifer Yellow showed that MSNs in Parkinson's disease group was significantly lower than that in saline group and the MSNs in dyskinesia model group recovered compared with Parkinson's disease model group,mainly manifested in the changes of mushroom spines,and the MSNs in eltoprazine group was higher than that in dyskinesia group.The main manifestations were the changes of mushroom and thin spines;(3)After stereotactic D1-mCherry-AAV,the results remain the same as(2);(4)In excitatory postsynaptic currents,the amplitude of postsynaptic membrane in PD group was higher than that in saline group,that in LID group was higher than that in PD group,and that in LID+ Elto group was higher than that in LID group.(5)the level of pERK in Parkinson's disease group was lower than that in saline group,and that in dyskinesia group was higher than that in Parkinson's disease group.Eltoprazine group recovered more than dyskinesia group.Conclusion:(1)Eltoprazine can significantly improve the levodopa-induced dyskinesia mice,especially begins at the first day(2)The dendritic spine density of medium spiny neurons in the dyskinesia group is higher than that in the Parkinson's disease group.The increase of mushroom spines density may compensate for the loss of dendritic spines in Parkinson's disease.The density of dendritic spines in eltoprazine group was higher than that in dyskinesia group.Combined with behavioral findings,it may be suggested that eltoprazine can improve LID by promoting the dendritic remodeling in striatum(3)D1 MSNs results show that eltoprazine can improve the remodeling of dendritic spines in striatum.Levodopa improves Parkinson's disease through D1 MSNs and Eltoprazine improves dyskinesia through D1 MSNs.(4)Dyskinesia may cause abnormal fluctuations through postsynaptic membrane,and eltoprazine can improve dyskinesia by improving excitatory postsynaptic currents amplitude.(5)pERK may be associated with dyskinesia and eltoprazine improving the D1 MSNs dendritic remodeling of dyskinesia. |
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