Experience-dependent changes in hippocampal spatial activity and hippocampal circuit function are disrupted in a rat model of Fragile X Syndrome.
Experience-dependent changes in hippocampal spatial activity and hippocampal circuit function are disrupted in a rat model of Fragile X Syndrome.
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DOI：
10.1186/s13229-022-00528-z
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发表时间：
2022-12-20
期刊：
影响因子：
6.2
通讯作者：
中科院分区：
文献类型：
--
作者：
脆性X综合征(FXS)是导致智力残疾和自闭症谱系障碍的常见单基因原因。认知缺乏灵活性是FXS的特征之一，受影响的人表现出极难适应新的或复杂的情况。为了探索这种认知缺乏灵活性的神经关联，我们使用了FXS的大鼠模型(Fmr1−/y)。我们记录了Fmr1−/y中的CA1和WT窝产仔在一个新的环境中进行了六次10分钟的探索-每天三次(ITI10分钟)。我们的记录分别从7只WT和7只Fmr1−/y大鼠获得了288个和246个推定的锥体细胞。在探索新环境的第一天，野生型(WT)大鼠和Fmr1−/y大鼠的CA1区锥体神经元的放电频率和空间调谐相似。然而，虽然WT大鼠的CA1区锥体神经元在暴露于环境的第一天和第二天之间表现出经验依赖性的放电和空间调谐变化，但Fmr1−/y大鼠的CA1区神经元的这些变化减少或消失。这些发现与体外培养的海马片中Fmr1−/yCA1神经元的兴奋性增加是一致的，这与内侧内嗅皮质的突触输入减少有关。最后，Fmr1−/y大鼠海马CA1区锥体神经元的活动模式与海马区的振荡活动不协调。目前尚不清楚观察到的回路功能异常如何导致Fmr1−/y大鼠的行为缺陷。未来的实验将集中在这种联系以及其他类型的神经细胞在与FMRP丢失相关的海马回路病理生理学中的作用。观察海马体回路缺陷是否会与其他智能障碍啮齿动物模型中的缺陷汇聚在一起，也是一件有趣的事情。总之，我们发现来自Fmr1−/y大鼠的海马区细胞表现出与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的空间特异性增加或网络协调性的经验依赖性变化。我们的发现支持了FXS认知缺陷的网络层面的起源。网上版载有补充材料，可在10.1186/s13229-022-00528-z查阅。
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). 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. 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. 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. 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. The online version contains supplementary material available at 10.1186/s13229-022-00528-z.
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影响因子：
16.2
作者：
Brandon MP;Koenig J;Leutgeb JK;Leutgeb S
通讯作者：
Leutgeb S
DOI：
10.1523/jneurosci.5110-11.2012
发表时间：
2012-05-23
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Ahmed OJ;Mehta MR
通讯作者：
Mehta MR
影响因子：
17.7
作者：
Bruno, Jennifer Lynn;Garrett, Amy S.;Reiss, Allan L.
通讯作者：
Reiss, Allan L.
DOI：
10.1093/cercor/bhw417
发表时间：
2017-02-01
期刊：
Cerebral cortex (New York, N.Y. : 1991)
影响因子：
--
作者：
Cooper RA;Richter FR;Bays PM;Plaisted-Grant KC;Baron-Cohen S;Simons JS
通讯作者：
Simons JS
影响因子：
3
作者：
Bokil, Hemant;Andrews, Peter;Kulkarni, Jayant E.;Mehta, Samar;Mitra, Partha P.
通讯作者：
Mitra, Partha P.