title: γ-aminobutyric acid type A receptors that contain the δ subunit promote memory and neurogenesis in the dentate gyrus.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Medical Science, University of Toronto, Ontario, Canada.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Whissell
authors.forename: Shira
authors.initials: S
authors.lastname: Rosenzweig
authors.forename: Irene
authors.initials: I
authors.lastname: Lecker
authors.forename: Dian-Shi
authors.initials: DS
authors.lastname: Wang
authors.forename: J Martin
authors.initials: JM
authors.lastname: Wojtowicz
authors.forename: Beverley A
authors.initials: BA
authors.lastname: Orser
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D018891:Dentate Gyrus / Q000502:physiology*; D004192:Discrimination, Psychological / Q000502:physiology; D004597:Electroshock / Q000009:adverse effects; D005106:Exploratory Behavior / Q000502:physiology; D018755:GABA Agonists / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D018782:Maze Learning; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000235:genetics*; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D021641:Recognition, Psychology / Q000502:physiology
chemical_list: D018755:GABA Agonists; D007555:Isoxazoles; D011963:Receptors, GABA-A; C015542:gaboxadol