San Martin Alvaro, Rela Lorena, Gelb Bruce, Pagani Mario Rafael
Instituto de Fisiología y Biofísica Bernardo Houssay, Grupo de Neurociencia de Sistemas, Facultad de Medicina, Universidad de Buenos Aires, The National Scientific and Technical Research Council, Buenos Aires C1121ABG, Argentina, and.
Mindich Child Health and Development Institute, Departments of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
J Neurosci. 2017 May 10;37(19):4992-5007. doi: 10.1523/JNEUROSCI.2607-16.2017. Epub 2017 Apr 21.
In contrast to trials of training without intervals (massed training), training trials spaced over time (spaced training) induce a more persistent memory identified as long-term memory (LTM). This phenomenon, known as the spacing effect for memory, is poorly understood. LTM is supported by structural synaptic plasticity; however, how synapses integrate spaced stimuli remains elusive. Here, we analyzed events of structural synaptic plasticity at the single-synapse level after distinct patterns of stimulation in motoneurons of We found that the spacing effect is a phenomenon detected at synaptic level, which determines the specificity and the precision in structural synaptic plasticity. Whereas a single pulse of stimulation (massed) induced structural synaptic plasticity, the same amount of stimulation divided in three spaced stimuli completely prevented it. This inhibitory effect was determined by the length of the interstimulus intervals. The inhibitory effect of the spacing was lost by suppressing the activity of Ras or mitogen-activated protein kinase, whereas the overexpression of Ras-WT enhanced it. Moreover, dividing the same total time of stimulation into five or more stimuli produced a higher precision in the number of events of plasticity. Ras mutations associated with intellectual disability abolished the spacing effect and led neurons to decode distinct stimulation patterns as massed stimulation. This evidence suggests that the spacing effect for memory may result from the effect of the spacing in synaptic plasticity, which appears to be a property not limited to neurons involved in learning and memory. We propose a model of spacing-dependent structural synaptic plasticity. Long-term memory (LTM) induced by repeated trials spaced over time is known as the spacing effect, a common property in the animal kingdom. Altered mechanisms in the spacing effect have been found in animal models of disorders with intellectual disability, such as Noonan syndrome. Although LTM is sustained by structural synaptic plasticity, how synapses integrate spaced stimuli and decode them into specific plastic changes remains elusive. Here, we show that the spacing effect is a phenomenon detected at the synaptic level, which determines the properties of the response in structural plasticity, including precision of such response. Whereas suppressing or enhancing Ras/mitogen-activated protein kinase signaling changed how synapses decode a pattern of stimuli, a disease-related Ras allele abolished the spacing effect for plastic changes.
与无间隔训练（集中训练）的试验相比，随时间间隔进行的训练试验（间隔训练）会诱导出一种更持久的记忆，即长时记忆（LTM）。这种现象，也就是记忆的间隔效应，目前还知之甚少。长时记忆由结构性突触可塑性支持；然而，突触如何整合间隔刺激仍然不清楚。在这里，我们分析了在不同刺激模式后运动神经元单突触水平上的结构性突触可塑性事件。我们发现间隔效应是一种在突触水平检测到的现象，它决定了结构性突触可塑性的特异性和精确性。单个刺激脉冲（集中刺激）会诱导结构性突触可塑性，而相同量的刺激分成三个间隔刺激则完全阻止了它。这种抑制作用由刺激间隔的长度决定。通过抑制Ras或丝裂原活化蛋白激酶的活性，间隔的抑制作用会消失，而Ras-WT的过表达则会增强它。此外，将相同的总刺激时间分成五个或更多刺激会在可塑性事件的数量上产生更高的精确性。与智力残疾相关的Ras突变消除了间隔效应，并导致神经元将不同的刺激模式解码为集中刺激。这一证据表明，记忆的间隔效应可能源于突触可塑性中间隔的作用，这似乎是一种不限于参与学习和记忆的神经元的特性。我们提出了一种依赖间隔的结构性突触可塑性模型。随时间间隔进行的重复试验诱导的长时记忆（LTM）被称为间隔效应，这是动物界的一个共同特性。在智力残疾疾病的动物模型中，如努南综合征，已经发现了间隔效应的改变机制。尽管长时记忆由结构性突触可塑性维持，但突触如何整合间隔刺激并将其解码为特定的可塑性变化仍然不清楚。在这里，我们表明间隔效应是一种在突触水平检测到的现象，它决定了结构性可塑性反应的特性，包括这种反应的精确性。抑制或增强Ras/丝裂原活化蛋白激酶信号会改变突触对刺激模式的解码方式，而与疾病相关的Ras等位基因则消除了可塑性变化的间隔效应。
