Medina Candela, de la Fuente Verónica, Tom Dieck Susanne, Nassim-Assir Belquis, Dalmay Tamas, Bartnik Ina, Lunardi Paula, de Oliveira Alvares Lucas, Schuman Erin M, Letzkus Johannes J, Romano Arturo
Instituto de Fisiología, Biología Molecular y Neurociencias, Departamento de Fisiología, Biología Molecular y Celular, CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina.
Instituto de Fisiología, Biología Molecular y Neurociencias, Departamento de Fisiología, Biología Molecular y Celular, CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina.
Neurobiol Learn Mem. 2020 Sep;173:107275. doi: 10.1016/j.nlm.2020.107275. Epub 2020 Jul 11.
Long-term memory has been associated with morphological changes in the brain, which in turn tightly correlate with changes in synaptic efficacy. Such plasticity is proposed to rely on dendritic spines as a neuronal canvas on which these changes can occur. Given the key role of actin cytoskeleton dynamics in spine morphology, major regulating factors of this process such as Cofilin 1 (Cfl1) and LIM kinase (LIMK), an inhibitor of Cfl1 activity, are prime molecular targets that may regulate dendritic plasticity. Using a contextual fear conditioning paradigm in mice, we found that pharmacological induction of depolymerization of actin filaments through the inhibition of LIMK causes an impairment in memory reconsolidation, as well as in memory consolidation. On top of that, Cfl1 activity is inhibited and its mRNA is downregulated in CA1 neuropil after re-exposure to the training context. Moreover, by pharmacological disruption of actin cytoskeleton dynamics, the process of memory extinction can either be facilitated or impaired. Our results lead to a better understanding of the role of LIMK, Cfl1 and actin cytoskeleton dynamics in the morphological and functional changes underlying the synaptic plasticity of the memory trace.
长期记忆与大脑中的形态变化相关，而形态变化又与突触效能的变化紧密相关。这种可塑性被认为依赖于树突棘，它是神经元上可发生这些变化的平台。鉴于肌动蛋白细胞骨架动力学在棘形态中的关键作用，该过程的主要调节因子，如丝切蛋白1（Cfl1）和Cfl1活性抑制剂LIM激酶（LIMK），是可能调节树突可塑性的主要分子靶点。利用小鼠的情境恐惧条件反射范式，我们发现通过抑制LIMK对肌动蛋白丝解聚进行药理学诱导会导致记忆再巩固以及记忆巩固受损。除此之外，重新暴露于训练情境后，CA1神经纤维网中Cfl1活性受到抑制，其mRNA表达下调。此外，通过药理学破坏肌动蛋白细胞骨架动力学，记忆消退过程既可以被促进也可以被损害。我们的结果有助于更好地理解LIMK、Cfl1和肌动蛋白细胞骨架动力学在记忆痕迹突触可塑性所涉及的形态和功能变化中的作用。
