Background: Extrasynaptic γ-aminobutyric acid type A receptors that contain the δ subunit (δGABAA receptors) are highly expressed in the dentate gyrus (DG) of the hippocampus, where they generate a tonic conductance that regulates activity. GABAA receptor-dependent signaling regulates memory and neurogenesis in the adult DG; however, the role of δGABAA receptors in these processes is unclear. Accordingly, it was postulated that δGABAA receptors regulate memory and neurogenesis in the DG.
Methods: A combination of genetic and pharmacologic techniques was employed. Memory in wild-type (WT) and δ subunit null (Gabrd–/–) mice was assessed using object-place recognition, novel object recognition, contextual discrimination, fear conditioning, fear extinction and water maze tasks. Long-term potentiation, a molecular correlate of memory, was examined using the in vitro hippocampal slice preparation. To ascertain the effects of enhanced δGABAA receptor activity, the receptor-preferring agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP; 4 mg/kg) was applied either as a pre-treatment (2 weeks prior to testing) or an acute treatment (30 min prior to testing).
Results: Gabrd–/– mice exhibited impaired object-place recognition, novel object recognition and contextual discrimination relative to WT mice. Further, Gabrd–/– mice exhibited impaired fear extinction, although fear acquisition was enhanced. Pre-treatment with THIP improved memory in WT but not Gabrd–/– mice. Consistent with these behavioural findings, neurogenesis was impaired in Gabrd–/– mice and enhanced in WT mice by pre-treatment with THIP. In contrast to the beneficial effects of pre-treatment with THIP, acute THIP impaired memory and long-term potentiation in WT mice.
Conclusions: These results indicate that δGABAA receptors promote memory and neurogenesis under baseline conditions. These processes may also be enhanced by long-term activation of δGABAA receptors with selective drugs, provided that these drug are absent during testing. Further, these findings show that acute activation of δGABAA receptors impairs memory and long-term potentiation.
Implications: δGABAA receptors may be a therapeutic target for the long-term treatment of memory dysfunction during aging, injury and disease. These findings also have clinical implications, as δGABAA receptors are molecular targets for therapeutic and recreational drugs. The acute amnestic effects of these compounds may be partially explained by δGABAA receptor activity.Ph
