Neurology Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USA.
Research Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USA.
Tremor Other Hyperkinet Mov (N Y). 2024 Apr 26;14:20. doi: 10.5334/tohm.834. eCollection 2024.
Essential tremor patients may find that low alcohol amounts suppress tremor. A candidate mechanism is modulation of α6β3δ extra-synaptic GABA receptors, that respond to non-intoxicating alcohol levels. We previously found that low-dose alcohol reduces harmaline tremor in wild-type mice, but not in littermates lacking δ or α6 subunits. Here we addressed whether low-dose alcohol requires the β3 subunit for tremor suppression.
We tested whether low-dose alcohol suppresses tremor in cre-negative mice with intact β3 exon 3 flanked by loxP, and in littermates in which this region was excised by cre expressed under the α6 subunit promotor. Tremor in the harmaline model was measured as a percentage of motion power in the tremor bandwidth divided by overall motion power.
Alcohol, 0.500 and 0.575 g/kg, reduced harmaline tremor compared to vehicle-treated controls in floxed β3 cre- mice, but had no effect on tremor in floxed β3 cre+ littermates that have β3 knocked out. This was not due to potential interference of α6 expression by the insertion of the cre gene into the α6 gene since non-floxed β3 cre+ and cre- littermates exhibited similar tremor suppression by alcohol.
As α6β3δ GABA receptors are sensitive to low-dose alcohol, and cerebellar granule cells express β3 and are the predominant brain site for α6 and δ expression together, our overall findings suggest alcohol acts to suppress tremor by modulating α6β3δ GABA receptors on these cells. Novel drugs that target this receptor may potentially be effective and well-tolerated for essential tremor.
We previously found with the harmaline essential tremor model that GABA receptors containing α6 and δ subunits mediate tremor suppression by alcohol. We now show that β3 subunits in α6-expressing cells, likely cerebellar granule cells, are also required, indicating that alcohol suppresses tremor by modulating α6β3δ extra-synaptic GABA receptors.
特发性震颤患者可能会发现少量酒精可抑制震颤。一个候选机制是调节α6β3δ 型突触外 GABA 受体，该受体对非致醉性酒精水平有反应。我们之前发现，低剂量酒精可减少野生型小鼠中哈尔明震颤，但缺乏 δ 或 α6 亚基的同窝仔鼠则没有。在此，我们研究了低剂量酒精是否需要β3 亚基来抑制震颤。
我们测试了低剂量酒精是否可抑制loxP 侧翼完整β3 外显子 3 的 cre- 缺失小鼠以及该区域由α6 亚基启动子驱动的 cre 表达而缺失β3 的同窝仔鼠的震颤。哈尔明模型中的震颤以震颤带宽内运动功率除以总运动功率的百分比来衡量。
与载体处理的对照组相比，0.500 和 0.575 g/kg 的酒精可降低 floxed β3 cre- 小鼠的哈尔明震颤，但对缺失β3 的 floxed β3 cre+ 同窝仔鼠的震颤没有影响。这不是由于 cre 基因插入到 α6 基因中而潜在干扰了α6 的表达，因为非 floxed β3 cre+ 和 cre- 同窝仔鼠的酒精抑制震颤作用相似。
由于 α6β3δ GABA 受体对低剂量酒精敏感，并且小脑颗粒细胞表达β3 亚基，并且是 α6 和 δ 共同表达的主要脑区，我们的总体发现表明，酒精通过调节这些细胞上的 α6β3δ GABA 受体来抑制震颤。针对该受体的新型药物可能对特发性震颤有效且耐受性良好。
我们之前在哈尔明特发性震颤模型中发现，含有 α6 和 δ 亚基的 GABA 受体介导酒精对震颤的抑制作用。我们现在表明，α6 表达细胞中的β3 亚基（可能是小脑颗粒细胞）也是必需的，这表明酒精通过调节α6β3δ 型突触外 GABA 受体来抑制震颤。
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