The principal finding of this study is that deletion of the GABAA
receptor α1 subunit results in a mouse with a persistent postural and kinetic tremor, characteristic of human essential tremor disease. Tremor was observed in the first generation of GABAA
) and has persisted through more than 9 generations of mice. Our first report on these mice (28
) failed to recognize the phenotype, probably owing to the focus on electrophysiological analysis rather than behavior. The tremor is easily observed in all 3 laboratories that currently breed the mice. Current drug therapy for essential tremor was efficacious in reducing tremor in α1–/–
mice. Furthermore, the tremor in α1–/–
mice responded to ethanol, MK-801, and CCPA, suggesting that glutamatergic and adenosinergic mechanisms are involved in the inhibitory effects of ethanol and are potential targets for novel pharmacotherapy. GABAA
mice exhibit a complete loss of both endogenous and exogenous GABA inhibition in cerebellar Purkinje cells. In addition, these mice exhibit the loss of 50% of all GABAA
receptor binding sites throughout the brain, including brain regions in the major motor pathways from the brainstem to the thalamus and the basal ganglia (21
). It is likely that loss of GABA inhibition in these motor pathways underlies tremor in α1–/–
There are many similarities between tremor in GABAA
mice and human essential tremor disease (Table ). Deletion of the GABAA
receptor α1 subunit produces a pathologic tremor with postural and kinetic components similar to essential tremor disorder. Furthermore, the tremor is genetic and persistent when compared with existing models that produce a chemical-induced tremor that is short-lived. Human physiologic and essential tremor occur at frequency ranges of 8–12 Hz and 4–8 Hz, respectively (29
). The higher frequency of both physiologic and pathologic tremor in rodents is probably due to the smaller size of the animal. The appearance of a pathologic tremor at 19 Hz, relative to the physiologic tremor frequency of 25–40 Hz in α1–/–
mice, is indicative of essential tremor rather than enhanced physiologic tremor.
GABAA receptor α1–/– mouse model reflects aspects of human essential tremor
The efficacy of drugs used in the treatment of human essential tremor was observed in α1–/–
mice, lending further support to the model. The ability of the first-line treatments, primidone and propranolol, to alleviate essential tremor in α1–/–
mice supports common mechanisms with human essential tremor. Furthermore, successful novel application of drugs such as the anticonvulsant gabapentin in both α1–/–
mice and patients demonstrates the necessity for animal models in which new and existing drugs can be screened for clinical utility (7
mice provide a useful animal model with which to investigate the pathophysiology of essential-like tremor and the mechanisms by which current and future therapies exert their effects.
Ethanol is effective in the suppression of essential tremor symptoms in humans and α1–/–
mice. Ethanol was the most effective treatment of tremor in α1–/–
mice at doses that preclude the contribution of its sedative effects on tremor (30
). Ethanol is believed to act centrally in the alleviation of tremor and, in human studies, has been shown to involve a central component (20
). Furthermore, positron emission tomography studies have shown that ethanol consumption increases cerebral blood flow in the inferior olivary nucleus, a central oscillator, which coincides with alleviation of tremor (31
The mechanism responsible for ethanol’s effects on tremor appears to involve inhibition of excitatory glutamatergic transmission but not activation of inhibitory GABAergic receptors. The efficacy of the glutamatergic antagonist MK-801 but not of GABAergic agonists diazepam and allopregnanolone suggest that the tremor may result from inactivation of inhibitory neurons. Although the lack of tremor inhibition by diazepam in α1–/–
mice is consistent with low responsiveness in patients with essential tremor (20
), the augmentation of tremor by diazepam was unexpected. Ethanol has several other targets in the brain that could account for its effects. Ethanol-sensitive adenosine receptors may be involved; however, studies with the adenosine agonist CCPA did not eliminate the possibility for peripheral effects of the drug, because significant motor incoordination was also observed in the mice.
Disruption of Purkinje cell function following deletion of GABAA
receptor α1 subunits likely contributes, in part, to the etiology of the tremor in α1–/–
mice. The loss of GABAergic inhibition on Purkinje cells suggests that α1 subunit expression is critical for normal function of motor circuits and likely contributes to tremor and motor incoordination observed in α1–/–
mice. Tremor induced by alcohol withdrawal is clinically similar to essential tremor and also results in decreased α1 subunit expression in rat cerebellum (32
). The lack of change in spontaneous activity of Purkinje cells is consistent with the lack of resting tremor and implies some adaptation to the loss of α1 subunits in these mice. Although compensatory changes in other GABAA
receptor subunits have been observed in some brain regions of α1–/–
), no GABAergic compensation in cerebellar Purkinje cells was found (data not shown). Because α1 subunits are normally expressed in other cells of this motor pathway, including the deep cerebellar nuclei and thalamus (but not the inferior olive), it is likely that communication among these regions is also disturbed by α1 subunit deletion and subsequent adaptations in receptor subunit expression. Although we have described altered GABA responses in the cerebellum, impairment of GABAergic inhibition is likely throughout the motor pathways that could contribute to the observed tremor. Additional studies will be required to determine if loss of α1 subunits in any single brain area is sufficient to mimic the clinical manifestations of human essential tremor disease. Furthermore, a common target of the major drugs used to treat essential tremor (primidone and propranolol) has not been elucidated. Therefore, treatment of essential tremor may target several pathways in the brain.
The similarities between human essential tremor and pathologic tremor in α1–/– mice suggest that expression of α1 subunits in the brains of patients with essential tremor may be abnormal. Further studies are needed to test this possibility. The GABAA receptor α1–/– mouse model of essential tremor provides a behavioral paradigm with predictive validity for testing novel potential treatments for this prevalent disorder.