Department of Psychology, SUNY Old Westbury, Old Westbury, NY, USA.
SUNY Neuroscience Research Institute, SUNY Old Westbury, Old Westbury, NY, USA.
Adv Exp Med Biol. 2017;975 Pt 1:39-55. doi: 10.1007/978-94-024-1079-2_4.
Lead (Pb) is a historically well-documented environmental neurotoxin that produces developmental cognitive learning and memory impairments. These early neurodevelopmental impairments cause increased brain excitability via disruption of Ca mediated signaling during critical periods of synaptogenesis inducing competition with I through NMDAs resulting in altered brain development and functioning across the lifespan. Interestingly, Pb has been shown to decrease GABA transport and uptake, decrease spontaneous and depolarization-evoked GABA neurotransmission and lower the expression of glutamic acid decarboxylase (GAD); thereby, limiting excitatory GABAergic influences that regulate early developmental brain excitability and reducing inhibition across mature GABAergic networks. Taurine has been shown to regulate brain excitability in the mature brain through GABA mediated inhibition, thereby attenuating improper brain excitability. Mechanistically, taurine is developmentally a potent neuromodulator that acts as a GABA agonist and more recently has been reported as a partial agonist for NMDAs through glycine sites. We investigated the effects of developmental Pb exposure on the rat's mature inhibitory cognitive control abilities pharmacologically through anxiety and emotional learning-related behaviors and whether taurine could recover Pb induced neurodevelopmental behavioral deficits later in life. Results showed that Pb increased anxiety symptoms in the open field and hole board test, increased sensitivity to context fear training with cognitive deficits in both acquisition and extinction learning while producing learning deficits and inabilities in acquiring inhibitory learned associations through the acoustic startle response and pre-pulse inhibition (ASR-PPI) test. Interestingly, taurine recovered Pb developmentally induced behavioral deficits in the open field and hole board test evidenced by decreased freezing and increased exploration behaviors and facilitated inhibitory dependent ASR-PPI learning to levels higher than controls. In contrast, Baclofen, a GABA agonist, dose dependently showed no interaction with Pb effects on ASR-PPI learning. Thus, taurine may work as an important neuromodulator at both GABAs and NMDAs glycine sites, thereby increasing inhibition, enhancing Ca-mediated signaling, and decreasing the altered brain excitability, which impedes learning and memory from early Pb exposure. Taken together our data suggests that GABA dependent inhibitory learning is altered by early Pb exposure and taurine was able to recover these Pb induced deficits through neuromodulation of GABAs and potentially NMDAs later in life. These findings may pave the way for further exploration of taurine as a pharmacotherapy for neurodevelopmental lead poisoning in both animal and clinical models.
铅（Pb）是一种历史上有充分记录的环境神经毒素，可导致发育认知学习和记忆障碍。这些早期的神经发育障碍通过在突触发生的关键时期破坏 Ca 介导的信号传导导致大脑兴奋性增加，通过 NMDA 与 I 竞争，导致大脑在整个生命周期中的发育和功能发生改变。有趣的是，Pb 已被证明可降低 GABA 转运和摄取，降低自发性和去极化诱发的 GABA 神经传递，并降低谷氨酸脱羧酶（GAD）的表达；从而限制调节早期发育大脑兴奋性的兴奋性 GABA 能影响，并减少成熟 GABA 能网络中的抑制作用。牛磺酸已被证明可通过 GABA 介导的抑制来调节成熟大脑的大脑兴奋性，从而减轻大脑兴奋性异常。从机制上讲，牛磺酸在发育过程中是一种有效的神经调节剂，可作为 GABA 激动剂，最近有报道称它通过甘氨酸位点作为 NMDA 的部分激动剂。我们通过焦虑和情绪学习相关行为，以及牛磺酸是否可以在以后的生活中恢复 Pb 引起的神经发育行为缺陷，研究了发育性 Pb 暴露对大鼠成熟抑制性认知控制能力的药理学影响。结果表明，Pb 在开阔场和洞板测试中增加了焦虑症状，增加了对上下文恐惧训练的敏感性，在获得和消退学习中都出现了认知缺陷，同时通过听觉惊吓反应和预脉冲抑制（ASR-PPI）测试产生了学习缺陷和无法获得抑制性习得关联。有趣的是，牛磺酸恢复了 Pb 在开阔场和洞板测试中引起的发育性行为缺陷，表现为冻结减少和探索行为增加，并促进了抑制性依赖的 ASR-PPI 学习，使其达到高于对照的水平。相比之下，GABA 激动剂 Baclofen 剂量依赖性地显示出与 Pb 对 ASR-PPI 学习的影响没有相互作用。因此，牛磺酸可能作为一种重要的神经调节剂，在 GABA 和 NMDA 的甘氨酸位点发挥作用，从而增加抑制作用，增强 Ca 介导的信号传导，并降低因早期 Pb 暴露而改变的大脑兴奋性，从而阻碍学习和记忆。总的来说，我们的数据表明，早期 Pb 暴露会改变 GABA 依赖性抑制性学习，而牛磺酸通过生命后期对 GABA 和潜在的 NMDA 的神经调节能够恢复这些 Pb 引起的缺陷。这些发现可能为进一步探索牛磺酸作为神经发育性铅中毒的药物治疗方法铺平道路，无论是在动物模型还是临床模型中。
