GABA_B(1) receptor isoforms differentially mediate the acquisition and extinction of aversive taste memories

Conditioned taste aversion (CTA) is a form of aversive memory in which an association is made between a consumed substance and a subsequent malaise. CTA is a critical mechanism for the successful survival, and hence evolution, of most animal species. The role of excitatory neurotransmitters in the neurochemical mechanisms of CTA is well recognized; however, less is known about the involvement of inhibitory receptor systems. In particular, the potential functions of metabotropic GABA_B receptors in CTA have not yet been fully explored. GABA_B receptors are metabotropic GABA receptors that are comprised of two subunits, GABA_B(1) and GABA_B(2), which form heterodimers. The Gabbr1 gene is transcribed into two predominant isoforms, GABA_B(1a) and GABA_B(1b), which differ in sequence primarily by the inclusion of a pair of sushi domains (alsoknownas short consensus repeats) in the GABA_B(1a) N terminus. The behavioral function of mammalian GABA_B(1) receptor isoforms is currently unknown. Here, using a point mutation strategy in mice, we demonstrate that these two GABA_B(1) receptor isoforms are differentially involved in critical components of CTA. In contrast to GABA_B(1b)^-/- and wild-type mice, GABA_B(1a)^-/- mice failed to acquire CTA. In contrast, GABA_B(1b)^-/- mice robustly acquired CTA but failed to show any extinction of this aversion. The data demonstrate that GABA_B receptors are involved in both the acquisition and extinction of CTA; however, receptors containing the GABA_B(1a) or the GABA _B(1b) isoform differentially contribute to the mechanisms used to learn and remember the salience of aversive stimuli.