School of Medicine, New York University, New York, NY 10016, USA.
Center for Neural Science, New York University, New York, NY 10003, USA.
Neuron. 2018 Feb 7;97(3):684-697.e4. doi: 10.1016/j.neuron.2017.12.043. Epub 2018 Jan 18.
Silence of FMR1 causes loss of fragile X mental retardation protein (FMRP) and dysregulated translation at synapses, resulting in the intellectual disability and autistic symptoms of fragile X syndrome (FXS). Synaptic dysfunction hypotheses for how intellectual disabilities like cognitive inflexibility arise in FXS predict impaired neural coding in the absence of FMRP. We tested the prediction by comparing hippocampus place cells in wild-type and FXS-model mice. Experience-driven CA1 synaptic function and synaptic plasticity changes are excessive in Fmr1-null mice, but CA1 place fields are normal. However, Fmr1-null discharge relationships to local field potential oscillations are abnormally weak, stereotyped, and homogeneous; also, discharge coordination within Fmr1-null place cell networks is weaker and less reliable than wild-type. Rather than disruption of single-cell neural codes, these findings point to invariant tuning of single-cell responses and inadequate discharge coordination within neural ensembles as a pathophysiological basis of cognitive inflexibility in FXS. VIDEO ABSTRACT.
FMR1 的沉默导致脆性 X 智力低下蛋白（FMRP）的丢失和突触翻译失调，从而导致脆性 X 综合征（FXS）的智力残疾和自闭症症状。FXS 中智力障碍（如认知灵活性受损）的突触功能障碍假说预测，在没有 FMRP 的情况下，神经编码会受损。我们通过比较野生型和 FXS 模型小鼠的海马体位置细胞来检验这一预测。在 Fmr1 基因敲除小鼠中，CA1 突触的功能和突触可塑性变化过度，但 CA1 位置场正常。然而，Fmr1 基因敲除小鼠的放电与局部场电位振荡的关系异常微弱、刻板且同质；此外，Fmr1 基因敲除小鼠的位置细胞网络内的放电协调比野生型小鼠更弱且不可靠。这些发现表明，作为 FXS 认知灵活性障碍的病理生理学基础，不是单个细胞神经编码的破坏，而是单个细胞反应的不变调谐和神经集合内放电协调的不足。视频摘要。
