Institute of Medical Science, University of Toronto, Ontario, Canada.
Ann Neurol. 2013 Oct;74(4):611-21. doi: 10.1002/ana.23941. Epub 2013 Jul 8.
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.
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.
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.
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.
含有 δ 亚基的突触外 γ-氨基丁酸 A 型受体（δGABAA 受体）在海马齿状回（DG）亚区高度表达，在那里产生调节神经元活动的紧张电导。GABAA 受体依赖性信号转导调节记忆，并且促进成年 DG 中的神经发生；然而，δGABAA 受体在这些过程中的作用尚不清楚。因此，我们试图确定 δGABAA 受体是否调节记忆行为以及 DG 中的神经发生。
在野生型（WT）小鼠和缺乏 δGABAA 受体（Gabrd(-/-)）的转基因小鼠中研究了记忆和神经发生。为了药理学增加 δGABAA 受体活性，用 δGABAA 受体优先激动剂 4,5,6,7-四氢异恶唑并[5,4-c]吡啶-3-醇（THIP）处理小鼠。使用识别记忆、上下文辨别和恐惧消退等行为测定来评估记忆。通过测量 DG 中成年新生神经元的增殖、存活、迁移、成熟和树突复杂性来研究神经发生。
与 WT 小鼠相比，Gabrd(-/-) 小鼠表现出识别记忆和上下文辨别受损。Gabrd(-/-) 小鼠的恐惧消退也受损，尽管恐惧记忆的获得增强。Gabrd(-/-) 小鼠的神经发生受损，因为成年新生神经元的迁移、成熟和树突发育受损。长期用 THIP 治疗促进 WT 小鼠的学习和神经发生，但不促进 Gabrd(-/-) 小鼠的学习和神经发生。
δGABAA 受体促进某些 DG 依赖性记忆行为的表现并促进神经发生。此外，可以对 δGABAA 受体进行药理学靶向以增强这些过程。
