Is essential tremor a disorder of primary GABA dysfunction? Yes.

Dysfunction in gamma-aminobutyric acid (GABA) neurotransmission has emerged as a prime suspect for the underlying neurochemical dysfunction in essential tremor (ET). This dysfunction has been termed the GABA hypothesis. We review findings to date supporting the 4 steps in this hypothesis in studies of cerebrospinal fluid, pathology, genetics, animal models, imaging, computational models, and human drugs, while not overlooking the evidence of negative studies and controversies. It remains to be elucidated whether reduced GABAergic tone is a primary contributing factor to ET pathophysiology, a consequence of altered Purkinje cell function, or even a result of Purkinje cell death. More studies are clearly needed to confirm both the neurodegenerative nature of ET and the reduction in GABA activity in the cerebellum. Also necessary is to test further therapies to enhance GABA transmission specifically focused on the cerebellar area.