γ-Aminobutyric Acid Type A Receptors That Contain the δ Subunit Promote Memory and Neurogenesis in the Dentate Gyrus

ObjectiveExtrasynaptic -aminobutyric acid type A receptors that contain the subunit (GABA(A) receptors) are highly expressed in the dentate gyrus (DG) subfield of the hippocampus, where they generate a tonic conductance that regulates neuronal activity. GABA(A) receptor-dependent signaling regulates memory and also facilitates postnatal neurogenesis in the adult DG; however, the role of the GABA(A) receptors in these processes is unclear. Accordingly, we sought to determine whether GABA(A) receptors regulate memory behaviors, as well as neurogenesis in the DG. MethodsMemory and neurogenesis were studied in wild-type (WT) mice and transgenic mice that lacked GABA(A) receptors (Gabrd(-/-)). To pharmacologically increase GABA(A) receptor activity, mice were treated with the GABA(A) receptor-preferring agonist 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP). Behavioral assays including recognition memory, contextual discrimination, and fear extinction were used. Neurogenesis was studied by measuring the proliferation, survival, migration, maturation, and dendritic complexity of adult-born neurons in the DG. ResultsGabrd(-/-) mice exhibited impaired recognition memory and contextual discrimination relative to WT mice. Fear extinction was also impaired in Gabrd(-/-) mice, although the acquisition of fear memory was enhanced. Neurogenesis was disrupted in Gabrd(-/-) mice as the migration, maturation, and dendritic development of adult-born neurons were impaired. Long-term treatment with THIP facilitated learning and neurogenesis in WT but not Gabrd(-/-) mice. InterpretationGABA(A) receptors promote the performance of certain DG-dependent memory behaviors and facilitate neurogenesis. Furthermore, GABA(A) receptors can be pharmacologically targeted to enhance these processes. Ann Neurol 2013;74:611-621