Specific roles of GABA(B(1)) receptor isoforms in cognition

Abstract

The GABA(B) receptor is a heterodimer of GABA(B(1)) and GABA(B(2)) subunits. There are two isoforms of the GABA(B(1)) subunit: GABA(B(1a)) and GABA(B(1b)). Recent studies with mutant mice suggest a differential role for the two GABA(B(1)) isoforms in behavioural processes. As pharmacological and genetic studies have implicated GABA(B) receptors in cognition we investigated the behaviour of GABA(B(1a))(-/-) and GABA(B(1b))(-/-) mice in different types of cognitive paradigms. GABA(B(1a))(-/-) and GABA(B(1b))(-/-) mice were both impaired relative to wildtype controls in a continuous spontaneous alternation behaviour test of working spatial memory. In contrast to the reported phenotype of GABA(B(1))(-/-) mice, however, neither GABA(B(1a))(-/-) nor GABA(B(1b))(-/-) mice were deficient in a passive avoidance task. On the other hand, GABA(B(1a))(-/-) mice were impaired in familiar and novel object recognition. We conclude that GABA(B(1)) isoforms contribute differentially to GABA(B) receptor-mediated cognitive processes.

Fig. 1

Number of stretch attend posture performed in an object recognition task by wildtype (n = 19), GABA_B(1a) ^−/− (n = 14) and GABA_B(1b) ^−/− (n = 18) mice towards a disc at initial presentation (Time = 0:00), to the same (clean) disc 10 min and 24 hr later (Time = 0:10 and 24:00, respectively) and to a novel cone-shaped object (Time 24:10). ***P < 0.001 vs Time 0:00 within genotype; ^###P < 0.001, ^##P < 0.01 versus Time 0:10 within genotype.

Fig. 2

Percentage of correct alternations (a.), number of correct alternations and total number of arms visited (b.) by wildtype (WT, n = 12), GABA_B(1a) ^−/− (1a^−/−, n = 9) and GABA_B(1b) ^−/− (1b^−/−, n = 9) mice in a Y-maze continuous spontaneous alternation task. ***P < 0.001, **P < 0.01, * P < 0.05 versus WT; ^#P < 0.05 versus 1a^−/−.

Fig. 3

Latency of wildtype (WT, n = 23), GABA_B(1a) ^−/− (1a^−/−, n = 17) and GABA_B(1b) ^−/− (1b^−/−, n = 18) mice to enter the dark compartment during training and 24 h later during retention testing in a one-trial step-through passive avoidance paradigm.