Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA.
Sci Rep. 2023 Oct 21;13(1):18005. doi: 10.1038/s41598-023-44121-7.
Glyphosate, a herbicide marketed as Roundup, is widely used but there are concerns this exposure could impair cognitive function. In the CA1 region of rat hippocampal slices, we investigated whether glyphosate alters synaptic transmission and long-term potentiation (LTP), a cellular model of learning and memory. Our hypothesis is that glyphosate alters neuronal function and impairs LTP induction via activation of pro-inflammatory processes. Roundup depressed excitatory synaptic potentials(EPSPs) in a dose-dependent manner with complete suppression at 2000 mg/L. At concentrations ≤ 20 mg/L Roundup did not affect basal transmission, but 4 mg/L Roundup administered for 30 min inhibited LTP induction. Acute administration of 10-100 μM glyphosate also inhibited LTP induction. Minocycline, an inhibitor of microglial activation, and TAK-242, an inhibitor of toll-like receptor 4 (TLR4), both overcame the inhibitory effects of 100 µM glyphosate. Similarly, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS), a different TLR4 antagonist, overcame the inhibitory effects. In addition, ISRIB (integrated stress response inhibitor) and quercetin, an inhibitor of endoplasmic reticulum stress, overcame the inhibitory effects. We also observed that in vivo glyphosate injection (16.9 mg/kg i.p.) impaired one-trial inhibitory avoidance learning. This learning deficit was overcome by TAK-242. These observations indicate that glyphosate can impair cognitive function through pro-inflammatory signaling in microglia.
草甘膦，一种作为农达（Roundup）销售的除草剂，被广泛使用，但人们担心这种接触可能会损害认知功能。在大鼠海马切片的 CA1 区域，我们研究了草甘膦是否会改变突触传递和长时程增强（LTP），这是学习和记忆的细胞模型。我们的假设是，草甘膦通过激活促炎过程改变神经元功能并损害 LTP 的诱导。农达以剂量依赖性方式抑制兴奋性突触后电位（EPSPs），在 2000mg/L 时完全抑制。在浓度≤20mg/L 时，农达不会影响基础传递，但 4mg/L 农达作用 30min 可抑制 LTP 诱导。急性给予 10-100μM 草甘膦也抑制 LTP 诱导。米诺环素，一种小胶质细胞激活抑制剂，以及 TAK-242，一种 Toll 样受体 4（TLR4）抑制剂，均可克服 100μM 草甘膦的抑制作用。同样，Rhodobacter sphaeroides（R. sphaeroides）的脂多糖（LPS-RS），一种不同的 TLR4 拮抗剂，也克服了抑制作用。此外，ISRIB（整合应激反应抑制剂）和槲皮素，内质网应激抑制剂，克服了抑制作用。我们还观察到，体内草甘膦注射（16.9mg/kg，腹腔内）损害了单次回避学习。这种学习缺陷被 TAK-242 克服。这些观察结果表明，草甘膦可以通过小胶质细胞中的促炎信号转导损害认知功能。
