Whissell PD, Rosenzweig S, Lecker I, Wang DS, Wojtowicz JM, Orser BA. (2013) Ann Neurol. 74(4):611-21.
OBJECTIVE: Extrasynaptic γ-aminobutyric acid type A receptors that contain the δ subunit (δGABAA receptors) are highly expressed in the dentate gyrus (DG) subfield of the hippocampus, where they generate a tonic conductance that regulates neuronal activity. GABAA receptor-dependent signaling regulates memory and also facilitates postnatal neurogenesis in the adult DG; however, the role of the δGABAA receptors in these processes is unclear. Accordingly, we sought to determine whether δGABAA 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 δGABAA receptors (Gabrd-/-). To pharmacologically increase δGABAA receptor activity, mice were treated with the δGABAA 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: δGABAA receptors promote the performance of certain DG-dependent memory behaviors and facilitate neurogenesis. Furthermore, δGABAA receptors can be pharmacologically targeted to enhance these processes.
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