Reduced Prefrontal Synaptic Connectivity and Disturbed Oscillatory Population Dynamics in the CNTNAP2 Model of Autism
Reduced Prefrontal Synaptic Connectivity and Disturbed Oscillatory Population Dynamics in the CNTNAP2 Model of Autism
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DOI：
10.1016/j.celrep.2019.05.006
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发表时间：
2019-05-28
期刊：
影响因子：
8.8
通讯作者：
Golshani, Peyman
中科院分区：
文献类型：
--
作者：
Lazaro, Maria T.;Taxidis, Jiannis;Golshani, Peyman
CNTNAP2的功能缺失突变在人类中引起一种综合征形式的自闭症谱系障碍，在小鼠中产生社交缺陷、重复行为和癫痫发作。然而，这些突变在细胞和电路水平上的功能影响仍然难以捉摸。通过激光扫描光刺激、全细胞记录和电子显微镜，我们发现Cntnap2基因敲除（KO）小鼠内侧前额叶皮层（mPFC） L2/3锥体神经元的兴奋性和抑制性突触输入显著减少，同时脊柱和突触减少，尽管树突复杂性和内在兴奋性正常。此外，mPFC局部场电位（LFPs）和体内单位峰值的记录显示，在运动过程中，抑制性神经元的活动增加，δ和θ振荡的锁相减少，相偏好延迟。兴奋性神经元在δ频率处表现出相似的相位调制变化。最后，在KO小鼠不活动期间，两两相关性增加。因此，减少的突触输入可能导致皮层集合中神经元放电的时间协调受到干扰。
Loss-of-function mutations in CNTNAP2 cause a syndromic form of autism spectrum disorder in humans and produce social deficits, repetitive behaviors, and seizures in mice. However, the functional effects of these mutations at cellular and circuit levels remain elusive. Using laser-scanning photostimulation, whole-cell recordings, and electron microscopy, we found a dramatic decrease in excitatory and inhibitory synaptic inputs onto L2/3 pyramidal neurons of the medial prefrontal cortex (mPFC) of Cntnap2 knockout (KO) mice, concurrent with reduced spines and synapses, despite normal dendritic complexity and intrinsic excitability. Moreover, recording of mPFC local field potentials (LFPs) and unit spiking in vivo revealed increased activity in inhibitory neurons, reduced phase-locking to delta and theta oscillations, and delayed phase preference during locomotion. Excitatory neurons showed similar phase modulation changes at delta frequencies. Finally, pairwise correlations increased during immobility in KO mice. Thus, reduced synaptic inputs can yield perturbed temporal coordination of neuronal firing in cortical ensembles.