A high degree of regional, temporal and molecular specificity is evident in the regulation of GABAergic signaling in stress-responsive circuitry, hampering the use of systemic GABAergic modulators for the treatment of stress-related psychopathology. Here we investigated the effectiveness of local intervention with the GABA synthetic enzymes GAD65 and GAD67 in the dorsal dentate gyrus (dDG) vs ventral DG (vDG) to alleviate anxiety-like behavior and stress-induced symptoms in the rat. We induced shRNA-mediated knock down of either GAD65 or GAD67 with lentiviral vectors microinjected into the dDG or vDG of young adult male rats and examined anxiety behavior, learning and memory performance. Subsequently we tested whether reducing GAD65 expression in the dDG would also confer resilience against juvenile stress-induced behavioral and physiological symptoms in adulthood. While knock down of either isoform in the vDG increased anxiety levels in the open field and the elevated plus maze tests, the knock down of GAD65, but not GAD67, in the dDG conferred a significant reduction in anxiety levels. Strikingly, this manipulation also attenuated juvenile stress evoked anxiety behavior, cognitive and synaptic plasticity impairments. Local GABAergic circuitry in the DG plays an important and highly region-specific role in control of emotional behavior and stress responding. Reduction of GAD65 expression in the dDG appears to provide resilience to juvenile stress-induced emotional and cognitive deficits, opening a new direction towards addressing a significant risk factor for developing stress and trauma-related psychopathologies later in life.

高度的区域、时间和分子特异性在压力反应电路中 GABA 能信号的调节中很明显，阻碍了系统性 GABA 能调节剂用于治疗压力相关的精神病理学。在这里，我们研究了用 GABA 合成酶 GAD65 和 GAD67 在背齿状回 (dDG)与腹侧 DG (vDG) 以减轻大鼠的焦虑样行为和压力引起的症状。我们将慢病毒载体显微注射到年轻成年雄性大鼠的 dDG 或 vDG 中，诱导 shRNA 介导的 GAD65 或 GAD67 敲低，并检查了焦虑行为、学习和记忆表现。随后，我们测试了降低 dDG 中 GAD65 的表达是否也会赋予对成年期青少年应激引起的行为和生理症状的恢复能力。虽然在开放场和高架十字迷宫测试中敲低 vDG 中的任一亚型会增加焦虑水平，但敲低 dDG 中的 GAD65 而不是 GAD67 则显着降低了焦虑水平。引人注目的是，这种操作还减轻了青少年压力引起的焦虑行为、认知和突触可塑性障碍。DG 中的局部 GABA 能回路在控制情绪行为和压力反应方面发挥着重要且高度区域特异性的作用。dDG 中 GAD65 表达的减少似乎为青少年压力引起的情绪和认知缺陷提供了弹性，为解决日后发展压力和与创伤相关的精神病理学的重要风险因素开辟了新的方向。