Neurosteroids have non-genomic rapid actions on the brain via inhibitory a-aminobutyric acid type A (GABA_A) receptors. These actions are potent and widespread. The actions of neurosteroids at neuronal level depend on the a, b and subunits of the receptor. We have produced a mouse line without GABA_A receptor-mediated synaptic inhibition on cerebellar Purkinje cells by cell type-specific ablation of the GABA_A receptor 2 subunit, leaving only low conductance extrasynaptic a-b GABA_A receptors. These mice showed no obvious motor phenotype (Wulff et al., 2007) and their GABA_A receptor distributions as assessed by t-butylbicyclophosphoro-[³⁵S]thionate autoradiography were similar to wild-type littermates. However, the motor-impairing effect of the neurosteroid 5b-pregnan-3a-ol-20-one in the rotarod test was dramatically increased in the mutant mice. By restoring the 2 subunit in Purkinje neurons, the neurosteroid sensitivity could be diminished to control level. The results suggest that neurosteroids are very efficacious potentiators of the remaining extrasynaptic a-b GABA_A receptors in this single neuronal population.

References: 

Wulff P, Goetz T, Leppä E, Linden AM, Renzi M, Swinny JD, Vekovischeva OY, Sieghart W, Somogyi P, Korpi ER, Farrant M, Wisden W 2007. Nat Neurosci 10, 923–29.