Propranolol Modulates Cerebellar Circuit Activity and Reduces Tremor

Abstract

Tremor is the most common movement disorder. Several drugs reduce tremor severity, but no cures are available. Propranolol, a β-adrenergic receptor blocker, is the leading treatment for tremor. However, the in vivo circuit mechanisms by which propranolol decreases tremor remain unclear. Here, we test whether propranolol modulates activity in the cerebellum, a key node in the tremor network. We investigated the effects of propranolol in healthy control mice and Car8wdl/wdl mice, which exhibit pathophysiological tremor and ataxia due to cerebellar dysfunction. Propranolol reduced physiological tremor in control mice and reduced pathophysiological tremor in Car8wdl/wdl mice to control levels. Open field and footprinting assays showed that propranolol did not correct ataxia in Car8wdl/wdl mice. In vivo recordings in awake mice revealed that propranolol modulates the spiking activity of control and Car8wdl/wdl Purkinje cells. Recordings in cerebellar nuclei neurons, the targets of Purkinje cells, also revealed altered activity in propranolol-treated control and Car8wdl/wdl mice. Next, we tested whether propranolol reduces tremor through β1 and β2 adrenergic receptors. Propranolol did not change tremor amplitude or cerebellar nuclei activity in β1 and β2 null mice or Car8wdl/wdl mice lacking β1 and β2 receptor function. These data show that propranolol can modulate cerebellar circuit activity through β-adrenergic receptors and may contribute to tremor therapeutics.

Cerebellar nuclei cells produce distinct pathogenic spike signatures in mouse models of ataxia, dystonia, and tremor

“…To test this, we used Car8 wdl/wdl mice. We previously showed that Car8 wdl/wdl mice exhibit a severe oscillatory tremor that can be reduced to control levels by treatment with the beta blocker drug propranolol (36), which is used to treat tremor in human patients. Car8 wdl/wdl mice also exhibit ataxia and dystonia, which are not normalized by propranolol (10,22,26,36).…”

“…We previously showed that Car8 wdl/wdl mice exhibit a severe oscillatory tremor that can be reduced to control levels by treatment with the beta blocker drug propranolol (36), which is used to treat tremor in human patients. Car8 wdl/wdl mice also exhibit ataxia and dystonia, which are not normalized by propranolol (10,22,26,36). We found that, before treatment, Car8 wdl/wdl mice exhibited a large proportion of neurons with the tremor signature (8/13).…”

“…We have previously tested these models and consider them as reliable archetypical models for cerebellar movement disorders (17,18,20). For the analyses, we reanalyzed previous recordings (18,20,29,36,78) in addition to newly acquired ones. We previously found that the recording duration used for parameter analyses influences the presentation of spike properties.…”

“…Tremor analysis: The amplitude and frequency of tremor before (baseline) and during optogenetic stimulation was measured using a custom-made tremor monitor as previously described (20,36,78)The mice were implanted with optical fibers targeted to the interposed nucleus as described above. LED drivers were connected to the implant via optical patch cables and placed above the tremor monitor chamber.…”

“…We first compared the spike activity between mouse models for ataxia (L7 Cre ;Vgat fl/fl , (Brown et al, 2020a;White et al, 2014)), dystonia (Ptf1a Cre/+ ;Vglut2 fl/fl , (Brown et al, 2022;White and Sillitoe, 2017)), and tremor (harmaline injection, (Brown et al, 2020a;Handforth, 2012)) (Figure 1A). We chose these three mouse models because of the reliability, severity, and high penetrance of the ataxic, dystonic, and tremor symptoms within each respective group.…”