Whissell PD, Rosenzweig S, Lecker I, Wang DS, Wojtowicz JM, Orser BA. (2013) Ann Neurol. 74(4):611-21.

Abstract

OBJECTIVE: Extrasynaptic γ-aminobutyric acid type A receptors that contain the δ subunit (δGABA_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 δGABA_A receptors in these processes is unclear. Accordingly, we sought to determine whether δGABA_A receptors regulate memory behaviors, as well as neurogenesis in the DG.

METHODS: Memory and neurogenesis were studied in wild-type (WT) mice and transgenic mice that lacked δGABA_A receptors (Gabrd^-/-). To pharmacologically increase δGABA_A receptor activity, mice were treated with the δGABA_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.

RESULTS: Gabrd^-/- 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.

INTERPRETATION: δGABA_A receptors promote the performance of certain DG-dependent memory behaviors and facilitate neurogenesis. Furthermore, δGABA_A receptors can be pharmacologically targeted to enhance these processes.

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