A Critical Role for α4βδ GABAA Receptors in Shaping Learning Deficits at Puberty in Mice

The onset of puberty defines a developmental stage when some learning processes are diminished, but the mechanism for this deficit remains unknown. We found that, at puberty, expression of inhibitory alpha 4 beta delta gamma-aminobutyric acid type A (GABA(A)) receptors (GABAR) increases perisynaptic to excitatory synapses in CA1 hippocampus. Shunting inhibition via these receptors reduced N-methyl-D-aspartate receptor activation, impairing induction of long-term potentiation (LTP). Pubertal mice also failed to learn a hippocampal, LTP-dependent spatial task that was easily acquired by delta-/- mice. However, the stress steroid THP (3 alpha OH-5 alpha[beta]-pregnan-20-one), which reduces tonic inhibition at puberty, facilitated learning. Thus, the emergence of alpha 4 beta delta GABARs at puberty impairs learning, an effect that can be reversed by a stress steroid.