| First Author | Handforth A | Year | 2024 |
| Journal | Tremor Other Hyperkinet Mov (N Y) | Volume | 14 |
| Pages | 20 | PubMed ID | 38681506 |
| Mgi Jnum | J:354271 | Mgi Id | MGI:7730979 |
| Doi | 10.5334/tohm.834 | Citation | Handforth A, et al. (2024) A Role for GABA(A) Receptor beta3 Subunits in Mediating Harmaline Tremor Suppression by Alcohol: Implications for Essential Tremor Therapy. Tremor Other Hyperkinet Mov (N Y) 14:20 |
| abstractText | BACKGROUND: Essential tremor patients may find that low alcohol amounts suppress tremor. A candidate mechanism is modulation of alpha6beta3delta extra-synaptic GABA(A) receptors, that in vitro 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 delta or alpha6 subunits. Here we addressed whether low-dose alcohol requires the beta3 subunit for tremor suppression. METHODS: We tested whether low-dose alcohol suppresses tremor in cre-negative mice with intact beta3 exon 3 flanked by loxP, and in littermates in which this region was excised by cre expressed under the alpha6 subunit promotor. Tremor in the harmaline model was measured as a percentage of motion power in the tremor bandwidth divided by overall motion power. RESULTS: Alcohol, 0.500 and 0.575 g/kg, reduced harmaline tremor compared to vehicle-treated controls in floxed beta3 cre- mice, but had no effect on tremor in floxed beta3 cre+ littermates that have beta3 knocked out. This was not due to potential interference of alpha6 expression by the insertion of the cre gene into the alpha6 gene since non-floxed beta3 cre+ and cre- littermates exhibited similar tremor suppression by alcohol. DISCUSSION: As alpha6beta3delta GABA(A) receptors are sensitive to low-dose alcohol, and cerebellar granule cells express beta3 and are the predominant brain site for alpha6 and delta expression together, our overall findings suggest alcohol acts to suppress tremor by modulating alpha6beta3delta GABA(A) receptors on these cells. Novel drugs that target this receptor may potentially be effective and well-tolerated for essential tremor. HIGHLIGHTS: We previously found with the harmaline essential tremor model that GABA(A) receptors containing alpha6 and delta subunits mediate tremor suppression by alcohol. We now show that beta3 subunits in alpha6-expressing cells, likely cerebellar granule cells, are also required, indicating that alcohol suppresses tremor by modulating alpha6beta3delta extra-synaptic GABA(A) receptors. |
