Adenosine A2a receptor antagonists attenuate striatal adaptations following dopamine depletion

被引:28
作者
Peterson, Jayms D. [1 ]
Goldberg, Joshua A. [1 ]
Surmeier, D. James [1 ]
机构
[1] Northwestern Univ, Dept Physiol, Feinberg Sch Med, Chicago, IL 60611 USA
关键词
Adenosine; Dopamine; A2a; D-2; Cholinergic interneuron; Medium spiny neuron; Striatopallidal; Patch clamp; Two photon laser scanning microscopy; Spine; Parkinson's disease; MEDIUM SPINY NEURONS; BASAL GANGLIA CIRCUITRY; CHOLINERGIC INTERNEURONS; PARKINSONS-DISEASE; A(2A) RECEPTORS; STRIATOPALLIDAL NEURONS; SYNAPTIC PLASTICITY; CA2+ CHANNELS; MODULATION; EXCITABILITY;
D O I
10.1016/j.nbd.2011.08.030
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The motor symptoms of Parkinson's disease (PD) are widely thought to arise from an imbalance in the activity of the two major striatal efferent pathways following the loss of dopamine (DA) signaling. In striatopallidal, indirect pathway spiny projection neurons (iSPNs), intrinsic excitability rises following the loss of inhibitory D2 receptor signaling. Because these receptors are normally counterbalanced by adenosine A2a adenosine receptors, antagonists of these receptors are being examined as an adjunct to conventional pharmacological therapies. However, little is known about the effects of sustained A2a receptor antagonism on striatal adaptations in PD models. To address this issue, the A2a receptor antagonist SCH58261 was systemically administered to DA-depleted mice. After 5 days of treatment, the effects of SCH58261 on iSPNs were examined in brain slices using electrophysiological and optical approaches. SCH58261 treatment did not prevent spine loss in iSPNs following depletion, but did significantly attenuate alterations in synaptic currents, spine morphology and dendritic excitability. In part, these effects were attributable to the ability of SCH58261 to blunt the effects of DA depletion on cholinergic interneurons, another striatal cell type that co-expresses A2a and D-2 receptors. Collectively, these results suggest that A2a receptor antagonism improves striatal function in PD models by attenuating iSPN adaptations to DA depletion. (C) 2011 Elsevier Inc. All rights reserved.
引用
收藏
页码:409 / 416
页数:8
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