Tiagabine Improves Hippocampal Long-Term Depression in Rat Pups Subjected to Prenatal Inflammation

Maternal inflammation during pregnancy is associated with the later development of cognitive and behavioral impairment in the offspring, reminiscent of the traits of schizophrenia or autism spectrum disorders. Hippocampal long-term potentiation and long-term depression of glutamatergic synapses are respectively involved in memory formation and consolidation. In male rats, maternal inflammation with lipopolysaccharide (LPS) led to a premature loss of long-term depression, occurring between 12 and 25 postnatal days instead of after the first postnatal month, and aberrant occurrence of long-term potentiation. We hypothesized this would be related to GABAergic system impairment. Sprague Dawley rats received either LPS or isotonic saline ip on gestational day 19. Male offspring's hippocampus was studied between 12 and 25 postnatal days. Morphological and functional analyses demonstrated that prenatal LPS triggered a deficit of hippocampal GABAergic interneurons, associated with presynaptic GABAergic transmission deficiency in male offspring. Increasing ambient GABA by impairing GABA reuptake with tiagabine did not interact with the low frequency-induced long-term depression in control animals but fully prevented its impairment in male offspring of LPS-challenged dams. Tiagabine furthermore prevented the aberrant occurrence of paired-pulse triggered long-term potentiation in these rats. Deficiency in GABA seems to be central to the dysregulation of synaptic plasticity observed in juvenile in utero LPS-challenged rats. Modulating GABAergic tone may be a possible therapeutic strategy at this developmental stage.

孕期母体炎症与后代认知及行为损害的后续发生密切相关，该特征与精神分裂症或孤独症谱系障碍（autism spectrum disorders）的表现高度相似。谷氨酸能突触（glutamatergic synapses）的海马长时程增强（long-term potentiation）与长时程抑制（long-term depression）分别参与记忆的形成与巩固过程。在雄性大鼠中，经脂多糖（lipopolysaccharide, LPS）诱导的母体炎症会引发长时程抑制的过早丧失：该异常出现于出生后12至25天，而非出生后1个月之后，同时还会伴随长时程增强的异常激活。我们推测该现象与γ-氨基丁酸能（GABAergic）系统功能受损存在关联。斯普拉格-道利（Sprague Dawley）大鼠在妊娠第19天经腹腔注射（intraperitoneal, ip）脂多糖或等渗生理盐水。研究人员于出生后12至25天期间对雄性后代的海马体开展分析。形态学与功能实验结果显示，产前暴露于脂多糖会导致雄性后代海马体中的γ-氨基丁酸能中间神经元（GABAergic interneurons）数量缺失，并伴随突触前γ-氨基丁酸能传递功能缺陷。通过噻加宾（tiagabine）抑制γ-氨基丁酸重摄取以提升胞外γ-氨基丁酸浓度，并未对对照组动物的低频诱导长时程抑制产生影响，但完全逆转了脂多糖暴露母鼠雄性后代的长时程抑制受损情况。此外，噻加宾还可阻断此类大鼠中双脉冲诱导的长时程增强异常出现。γ-氨基丁酸缺乏似乎是宫内脂多糖暴露幼鼠突触可塑性失调的核心机制。在该发育阶段调节γ-氨基丁酸能系统的紧张性活动，或可成为一种潜在的治疗策略。