In the most general sense, however, the GABAA
receptor α1 knockout model is indeed essential, since knockout models of other GABAA receptor subunits (e.g., α5, α6, β2, β3, γ2,) do not display tremor, nor do models containing gene deletions impairing other steps in GABAergic transmission, including GABA synthesis (17
). It is also interesting that deletion of the GABAA receptor α1 gene leads to tremor, since point mutations in the same and related subunits of this gene give rise to entirely different human phenotypes that lack tremor but induce epilepsy (18
Assuming that a subset of clinical ET disorders linked to defective GABAergic α1 subunit receptors is ultimately identified in humans, what does this new mouse model tell us about GABA neurotransmission and tremor circuitry? Can it help us localize the site and determine the onset of the excitability defect? Not easily. Since the GABAA receptor α1 subunit is normally switched on at birth and combines with other α, β, and γ subunits to form the pentameric ligand-gated chloride ion channel mediating GABAergic inhibition throughout the neuraxis, considerable analysis will be required to explain the highly selective mechanism for delayed-onset tremor.
The most prevalent GABAA
receptor population in the brain is the pentamer containing subunits α1, α1, β, β, and γ (20
). In the absence of the α1 subunit, alternative members of the α subunit family are substituted in the cells where these receptors are normally expressed (Figure ). This means that all remaining GABAergic transmission in the GABAA
receptor α1–deficient mouse relies upon a mixture of GABAA receptors that in many cells are composed of novel α2–3/β, β/γ subunit combinations. Since these alternative receptors vary in kinetic behavior and pharmacology according to cell type and region, characterizing inhibitory transmission in the mutant nervous system will be a lengthy process, and the design of an effective drug to target this altered pattern may be dependent upon both age and region (21
). The authors postulate that the tremor in GABAA receptor α1–/–
mice may result from a loss of GABAA signaling by cerebellar purkinje cells but without actual degeneration of the cells (14
). This would be consistent with the pathological studies in ET, which have so far not demonstrated microscopic cerebellar pathology in postmortem brains of patients with ET (22
). It should be noted, however, that the GABAA receptor α1 mutant mice have an overall reduction in brain size of about 15%, limiting the ability to directly attribute the tremor to this specific purkinje cell–signaling defect.
Molecular architecture of a GABAergic synapse showing alternative subunit switching in the GABAA receptor α1–/– mouse.