Affective and cognitive effects of global deletion of α3-containing gamma-aminobutyric acid-A receptors

Gamma-aminobutyric acid (GABA)(A) receptors characterized by the presence of the alpha 3 subunit are the major GABA(A) receptor subtype expressed in brain stem monoaminergic nuclei. These alpha 3-GABA(A) receptors are therefore in a unique position to regulate monoaminergic functions. To characterize the functional properties of alpha 3-GABA(A) receptors, we present a preliminary assessment of the expression of affective and cognitive behaviour in male mice with a targeted deletion of the Gabra3 gene encoding the alpha 3 subunit [alpha 3 knockout (KO) mice] on a C57BL/6J x 1 29X1 /SvJ F1 hybrid genetic background. The alpha 3 KO mice did not exhibit any gross change of anxiety-like behaviour or spontaneous locomotor behaviour. In the Porsolt forced swim test for potential antidepressant activity, alpha 3 KO mice exhibited reduced floating and enhanced swimming behaviour relative to wild-type controls. Performance on a two-choice sucrose preference test, however, revealed no evidence for an increase in sucrose preference in the alpha 3 KO mice that would have substantiated a potential phenotype for depression-related behaviour. In contrast, a suggestion of an enhanced negative contrast effect was revealed in a one-bottle sucrose consumption test across different sucrose concentrations. These affective phenotypes were accompanied by alterations in the balance between conditioned responding to the discrete conditioned stimulus and to the context, and a suggestion of faster extinction, in the Pavlovian conditioned freezing paradigm. Spatial learning in the water maze reference memory test, however, was largely unchanged in the alpha 3 KO mice, except for a trend of preservation during reversal learning. The novel phenotypes following global deletion of the GABA(A) receptor alpha 3 subunit identified here provided relevant insights, in addition to our earlier study, into the potential behavioural relevance of this specific receptor subtypes in the modulation of both affective and cognitive functions.