Muñoz M Dolores, Antolín-Vallespín Mónica, Tapia-González Silvia, Sánchez-Capelo Amelia
Unidad de Neurología Experimental, Hospital Universitario Ramón y Cajal - IRYCIS, Madrid, Spain.
CIBERNED - Ser. Neurobiología - Investigación, Hospital Universitario Ramón y Cajal - IRYCIS, Madrid, Spain.
J Neurochem. 2016 Apr;137(2):190-9. doi: 10.1111/jnc.13558. Epub 2016 Feb 18.
Transforming growth factor-β signaling through intracellular Smad3 has been implicated in Parkinson's disease (PD) and it fulfills an important role in the neurogenesis and synaptic plasticity that occurs in the adult dentate gyrus (DG). The long-term potentiation (LTP) induced in the DG by high-frequency stimulation of the medial perforant pathway is abolished in the DG of Smad3-deficient mice, but not in the CA1 hippocampal region. Here, we show that NMDA- and AMPA-type glutamate receptors do not participate in the inhibition of LTP associated with Smad3 deficiency. Moreover, there is no difference in the hippocampal GAD65 and GAD67 content, suggesting that GABA biosynthesis remains unaffected. Increased conductance and higher action potential firing thresholds were evident in intracellular recordings of granule cells from Smad3 deficient mice. Interestingly, phasic and tonic GABAA receptor (GABAA R)-mediated neurotransmission is enhanced in the DG of Smad3-deficient mice, and LTP induction can be rescued by inhibiting GABAA R with picrotoxin. Hence, Smad3 signaling in the DG appears to be necessary to induce LTP by regulating GABAA neurotransmission, suggesting a central role of this intracellular signaling pathway in the hippocampal brain plasticity related to learning and memory. Smad3 deficient mice represent a new and interesting model of Parkinson's disease, displaying hippocampal dysfunctions that include decreased neurogenesis and the failure to induce LTP in the dentate gyrus. Here we show that Smad3 deficiency inhibits LTP induction by enhancing phasic and tonic GABAA receptor-mediated neurotransmission, while LTP induction can be rescued with a GABAA receptor antagonist. Alteration of GABA neurotransmission is thought to produce hippocampal cognitive dysfunction in Down's syndrome or Alzheimer's disease, and here we provide new insights into the hippocampal changes in an animal model of Parkinson's disease.
通过细胞内Smad3介导的转化生长因子-β信号传导与帕金森病（PD）有关，并且在成年齿状回（DG）发生的神经发生和突触可塑性中发挥重要作用。内侧穿通通路高频刺激在DG中诱导的长时程增强（LTP）在Smad3缺陷小鼠的DG中被消除，但在海马CA1区未被消除。在这里，我们表明NMDA型和AMPA型谷氨酸受体不参与与Smad3缺陷相关的LTP抑制。此外，海马GAD65和GAD67含量没有差异，这表明GABA生物合成未受影响。在Smad3缺陷小鼠颗粒细胞的细胞内记录中，电导增加和动作电位发放阈值升高很明显。有趣的是，在Smad3缺陷小鼠的DG中，相位性和紧张性GABAA受体（GABAA R）介导的神经传递增强，并且用印防己毒素抑制GABAA R可以挽救LTP诱导。因此，DG中的Smad3信号传导似乎是通过调节GABAA神经传递来诱导LTP所必需的，这表明该细胞内信号通路在与学习和记忆相关的海马脑可塑性中起核心作用。Smad3缺陷小鼠代表了一种新的有趣的帕金森病模型，表现出海马功能障碍，包括神经发生减少和齿状回中无法诱导LTP。在这里，我们表明Smad3缺陷通过增强相位性和紧张性GABAA受体介导的神经传递来抑制LTP诱导，而用GABAA受体拮抗剂可以挽救LTP诱导。GABA神经传递的改变被认为会在唐氏综合征或阿尔茨海默病中产生海马认知功能障碍，在这里我们为帕金森病动物模型中的海马变化提供了新的见解。
