Antonis Asiminas, Sam A Booker, Owen R Dando, Zrinko Kozic, Daisy Arkell, Felicity H Inkpen, Anna Sumera, Irem Akyel, Peter C Kind, Emma R Wood
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引用次数: 5
摘要
背景:脆性X染色体综合征(Fragile X syndrome, FXS)是智力残疾和自闭症谱系障碍的常见单基因病因。认知缺乏灵活性是FXS的特征之一,受影响的个体表现出极端难以适应新的或复杂的情况。为了探索这种认知不灵活性的神经相关性,我们使用了大鼠FXS模型(Fmr1-/y)。方法:我们记录了Fmr1-/y和WT幼崽的CA1,在一个新的环境中进行了6次10分钟的探索,每天3次(ITI 10分钟)。我们的记录分别从7只WT和7只Fmr1-/y大鼠中获得288和246个假定的锥体细胞。结果:在探索新环境的第一天,野生型(WT)和Fmr1-/y大鼠CA1锥体神经元的放电速率和空间调谐相似。然而,虽然WT大鼠的CA1锥体神经元在暴露于环境的第一天和第二天表现出经验依赖性的放电和空间调节变化,但Fmr1-/y大鼠的CA1神经元中这些变化减少或不存在。这些发现与离体海马切片中Fmr1-/y CA1神经元的兴奋性增加一致,这与来自内侧内嗅皮层的突触输入减少有关。最后,Fmr1-/y大鼠CA1锥体神经元的活动模式与海马振荡活动不协调。局限性:目前尚不清楚观察到的回路功能异常是如何引起Fmr1-/y大鼠的行为缺陷的。未来的实验将集中在这种联系以及与FMRP丧失相关的海马回路病理生理中其他神经细胞类型的贡献。看看海马体回路缺陷是否与其他智力残疾啮齿类动物模型中的缺陷趋同,也将是一件有趣的事情。结论:综上所述,我们发现Fmr1-/y大鼠海马位置细胞表现出与WT大鼠相似的空间放电特性,但没有表现出相同的经验依赖性空间特异性增加或网络协调性的经验依赖性变化。我们的研究结果为FXS认知缺陷的网络层面起源提供了支持。
Experience-dependent changes in hippocampal spatial activity and hippocampal circuit function are disrupted in a rat model of Fragile X Syndrome.
Background: Fragile X syndrome (FXS) is a common single gene cause of intellectual disability and autism spectrum disorder. Cognitive inflexibility is one of the hallmarks of FXS with affected individuals showing extreme difficulty adapting to novel or complex situations. To explore the neural correlates of this cognitive inflexibility, we used a rat model of FXS (Fmr1-/y).
Methods: We recorded from the CA1 in Fmr1-/y and WT littermates over six 10-min exploration sessions in a novel environment-three sessions per day (ITI 10 min). Our recordings yielded 288 and 246 putative pyramidal cells from 7 WT and 7 Fmr1-/y rats, respectively.
Results: On the first day of exploration of a novel environment, the firing rate and spatial tuning of CA1 pyramidal neurons was similar between wild-type (WT) and Fmr1-/y rats. However, while CA1 pyramidal neurons from WT rats showed experience-dependent changes in firing and spatial tuning between the first and second day of exposure to the environment, these changes were decreased or absent in CA1 neurons of Fmr1-/y rats. These findings were consistent with increased excitability of Fmr1-/y CA1 neurons in ex vivo hippocampal slices, which correlated with reduced synaptic inputs from the medial entorhinal cortex. Lastly, activity patterns of CA1 pyramidal neurons were dis-coordinated with respect to hippocampal oscillatory activity in Fmr1-/y rats.
Limitations: It is still unclear how the observed circuit function abnormalities give rise to behavioural deficits in Fmr1-/y rats. Future experiments will focus on this connection as well as the contribution of other neuronal cell types in the hippocampal circuit pathophysiology associated with the loss of FMRP. It would also be interesting to see if hippocampal circuit deficits converge with those seen in other rodent models of intellectual disability.
Conclusions: In conclusion, we found that hippocampal place cells from Fmr1-/y rats show similar spatial firing properties as those from WT rats but do not show the same experience-dependent increase in spatial specificity or the experience-dependent changes in network coordination. Our findings offer support to a network-level origin of cognitive deficits in FXS.
期刊介绍:
Molecular Autism is a peer-reviewed, open access journal that publishes high-quality basic, translational and clinical research that has relevance to the etiology, pathobiology, or treatment of autism and related neurodevelopmental conditions. Research that includes integration across levels is encouraged. Molecular Autism publishes empirical studies, reviews, and brief communications.