Local cortical circuit correlates of altered EEG in the mouse model of Fragile X syndrome
Local cortical circuit correlates of altered EEG in the mouse model of Fragile X syndrome
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DOI：
10.1016/j.nbd.2019.01.002
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发表时间：
2019-04-01
影响因子：
6.1
通讯作者：
Gibson, Jay R.
中科院分区：
文献类型：
--
作者：
Goswami, Sonal;Cavalier, Sheridan;Gibson, Jay R.
脆性 X 综合征 (FXS) 患者的脑电图 (EEG) 记录显示，感觉反应增强，静息“伽马频率”(30-100 Hz) 活动增强，以及感觉刺激调节伽马频率皮质活动的能力下降。在 FXS 模型小鼠（Fmr1 敲除）中观察到类似的变化。这些改变可能成为诊断和治疗 FXS 的有效生物标志物。因此，更好地了解这些变化背后的电路特性至关重要。我们利用视紫红质通道以光学方式激活大脑切片中听觉皮层区域的局部回路，以检查局部回路功能的变化与脑电图变化之间的关系。我们重点关注第 2/3 层和第 5 层（L2/3 和 L5）。在 Fmr1 敲除小鼠中，L2/3 的光驱动激发显示出局部 L2/3 和 L5 回路的过度兴奋性和伽马频率功率的增加。此外，L2/3 和 L5 之间的伽马频带的同步性有所增加。在 L5 光驱动激发的 L5 中没有观察到过度兴奋和伽马功率增加，这表明这些变化是层特异性的。 L2/3 网络过度兴奋性的一个组成部分独立于离子型受体介导的突触传递，并且可能由 L2/3 神经元的内在兴奋性增加介导。最后，洛伐他汀（一种针对 ERK 信号传导的 FXS 候选治疗化合物）并未使 γ 活性的变化正常化。总之，局部新皮质回路的过度活跃和伽马活性增加，以及回路之间伽马同步性的增加，为 FXS 患者和 FXS 小鼠模型中观察到的脑电图改变提供了假定的基础。
Electroencephalogram (EEG) recordings in Fragile X syndrome (FXS) patients have revealed enhanced sensory responses, enhanced resting "gamma frequency" (30-100 Hz) activity, and a decreased ability for sensory stimuli to modulate cortical activity at gamma frequencies. Similar changes are observed in the FXS model mouse - the Fmr1 knockout. These alterations may become effective biomarkers for diagnosis and treatment of FXS. Therefore, it is critical to better understand what circuit properties underlie these changes. We employed Channelrhodopsin2 to optically activate local circuits in the auditory cortical region in brain slices to examine how changes in local circuit function may be related to EEG changes. We focused on layers 2/3 and 5 (L2/3 and L5). In Fmr1 knockout mice, light-driven excitation of L2/3 revealed hyperexcitability and increased gamma frequency power in both local L2/3 and L5 circuits. Moreover, there is increased synchrony in the gamma frequency band between L2/3 and L5. Hyperexcitability and increased gamma power were not observed in L5 with L5 light-driven excitation, indicating that these changes were layer-specific. A component of L2/3 network hyperexcitability is independent of ionotropic receptor mediated synaptic transmission and may be mediated by increased intrinsic excitability of L2/3 neurons. Finally, lovastatin, a candidate therapeutic compound for FXS that targets ERK signaling did not normalize changes in gamma activity. In conclusion, hyperactivity and increased gamma activity in local neocortical circuits, together with increased gamma synchrony between circuits, provide a putative substrate for EEG alterations observed in both FXS patients and the FXS mouse model.