Kramvis Ioannis, Mansvelder Huibert D, Loos Maarten, Meredith Rhiannon
Department of Integrative Neurophysiology, Centre for Neurogenomics and Cognitive Research, VU University Amsterdam Amsterdam, Netherlands ; Sylics (Synaptologics BV) Amsterdam, Netherlands.
Front Behav Neurosci. 2013 Nov 21;7:172. doi: 10.3389/fnbeh.2013.00172. eCollection 2013.
Attentional deficits and executive function impairments are common to many neurodevelopmental disorders of intellectual disability and autism, including Fragile X syndrome (FXS). In the knockout mouse model for FXS, significant changes in synaptic plasticity and connectivity are found in the prefrontal cortex (PFC)-a prominent region for attentional processing and executive control. Given these alterations in PFC synaptic function, we tested whether adult Fragile X knockout mice exhibited corresponding impairments in inhibitory control, perseveration, and sustained attention. Furthermore, we investigated individual performance during attentional rule acquisition. Using the 5-choice serial reaction time task, our results show no impairments in inhibitory control and sustained attention. Fragile X knockout mice exhibited enhanced levels of correct and incorrect responding, as well as perseveration of responding during initial phases of rule acquisition, that normalized with training. For both knockout and wild type mice, pharmacological attenuation of metabotropic glutamate receptor 5 signaling did not affect response accuracy but reduced impulsive responses and increased omission errors. Upon rule reversal, Fragile X knockout mice made more correct and incorrect responses, similar to the initial phases of rule acquisition. Analogous to heightened activity upon novel rule acquisition, Fragile X knockout mice were transiently hyperactive in both a novel open field (OF) arena and novel home cage. Hyperactivity ceased with familiarization to the environment. Our findings demonstrate normal inhibitory control and sustained attention but heightened perseveration, responding, and hyperactivity during novel rule acquisition and during exposure to novel environments in Fragile X knockout mice. We therefore provide evidence for subtle but significant differences in the processing of novel stimuli in the mouse model for the FXS.
注意力缺陷和执行功能障碍在许多智力残疾和自闭症的神经发育障碍中很常见，包括脆性X综合征（FXS）。在FXS基因敲除小鼠模型中，前额叶皮层（PFC）——注意力处理和执行控制的一个重要区域——的突触可塑性和连接性发生了显著变化。鉴于PFC突触功能的这些改变，我们测试了成年脆性X基因敲除小鼠在抑制控制、持续性和持续注意力方面是否表现出相应的损伤。此外，我们还研究了注意力规则习得过程中的个体表现。使用5选串行反应时间任务，我们的结果表明在抑制控制和持续注意力方面没有损伤。脆性X基因敲除小鼠在规则习得的初始阶段表现出正确和错误反应水平的提高，以及反应的持续性，这些在训练后恢复正常。对于基因敲除小鼠和野生型小鼠，代谢型谷氨酸受体5信号的药理学减弱不影响反应准确性，但减少了冲动反应并增加了遗漏错误。在规则反转时，脆性X基因敲除小鼠做出了更多正确和错误的反应，类似于规则习得的初始阶段。与新规则习得时的活动增强类似，脆性X基因敲除小鼠在新的开放场（OF）区域和新的家笼中都短暂地过度活跃。随着对环境的熟悉，过度活跃停止。我们的研究结果表明，脆性X基因敲除小鼠在新规则习得期间和暴露于新环境时，抑制控制和持续注意力正常，但持续性、反应性和过度活跃增强。因此，我们为FXS小鼠模型中新型刺激处理的细微但显著差异提供了证据。
