Enhanced histamine H2 excitation of striatal cholinergic interneurons in L-DOPA-induced dyskinesia.

Levodopa is the most effective therapy for the motor deficits of Parkinson's disease (PD), but long term treatment leads to the development of L-DOPA-induced dyskinesia (LID). Our previous studies indicate enhanced excitability of striatal cholinergic interneurons (ChIs) in mice expressing LID and reduction of LID when ChIs are selectively ablated. Recent gene expression analysis indicates that stimulatory H2 histamine receptors are prefentially expressed on ChIs at high levels in the striatum, and we tested whether a change in H2 receptor function might contribute to the elevated excitability in LID. Using two different mouse models of PD (6-hydroxydopamine lesion and Pitx3ak/ak mutation), we chronically treated the animals with either vehicle or L-DOPA to induce dyskinesia. Electrophysiological recordings indicate that histamine H2 receptor-mediated excitation of striatal ChIs is enhanced in mice expressing LID. Additionally, H2 receptor blockade by systemic administration of famotidine decreases behavioral LID expression in dyskinetic animals. These findings suggest that ChIs undergo a pathological change in LID with respect to histaminergic neurotransmission. The hypercholinergic striatum associated with LID may be dampened by inhibition of H2 histaminergic neurotransmission. This study also provides a proof of principle of utilizing selective gene expression data for cell-type-specific modulation of neuronal activity.

左旋多巴是治疗帕金森病（PD）运动障碍最有效的疗法，但长期治疗会导致左旋多巴诱导的异动症（LID）的发生。我们之前的研究表明，在表现出LID的小鼠中，纹状体胆碱能中间神经元（ChIs）的兴奋性增强，并且当ChIs被选择性消融时，LID会减轻。近期的基因表达分析表明，刺激性H2组胺受体在纹状体的ChIs上高水平优先表达，我们测试了H2受体功能的改变是否可能导致LID中兴奋性升高。利用两种不同的帕金森病小鼠模型（6 - 羟基多巴胺损伤和Pitx3ak/ak突变），我们用赋形剂或左旋多巴对动物进行长期治疗以诱导异动症。电生理记录表明，在表现出LID的小鼠中，组胺H2受体介导的纹状体ChIs的兴奋增强。此外，通过法莫替丁全身给药阻断H2受体可减少异动症动物的行为性LID表现。这些发现表明，在组胺能神经传递方面，ChIs在LID中发生了病理变化。与LID相关的高胆碱能纹状体可能通过抑制H2组胺能神经传递而被抑制。这项研究也为利用选择性基因表达数据对神经元活动进行细胞类型特异性调节提供了原理验证。