BACKGROUND A breakdown of synchrony within neuronal ensembles leading to destabilization of network "attractors" could be a defining aspect of neuropsychiatric diseases such as schizophrenia, representing a common downstream convergence point for the diverse etiological pathways associated with the disease. Using a mouse genetic model, we demonstrated that altered ensembles are associated with pathological sensory cortical processing phenotypes resulting from loss of function mutations in the Setd1a gene, a recently identified rare risk genotype with very high penetrance for schizophrenia. METHODS We used fast 2-photon calcium imaging of neuronal populations (calcium indicator GCaMP6s, 10 Hz, 100-250 cells, layer 2/3 of primary visual cortex, i.e., V1) in awake head-fixed mice (Setd1a+/- vs. wild-type littermate control) during rest and visual stimulation with moving full-field square-wave gratings (0.04 cycles per degree, 2.0 cycles per second, 100% contrast, 12 directions). Multielectrode recordings were analyzed in the time-frequency domain to assess stimulus-induced oscillations and cross-layer phase synchrony. RESULTS Neuronal activity and orientation/direction selectivity were unaffected in Setd1a+/- mice, but correlations between cell pairs in V1 showed altered distributions compared with wild-type mice, in both ongoing and visually evoked activity. Furthermore, population-wide "ensemble activations" in Setd1a+/- mice were markedly less reliable over time during rest and visual stimulation, resulting in unstable encoding of basic visual information. This alteration of ensembles coincided with reductions in alpha and high-gamma band phase synchrony within and between cortical layers. CONCLUSIONS These results provide new evidence for an ensemble hypothesis of schizophrenia and highlight the utility of Setd1a+/- mice for modeling sensory-processing phenotypes.

中文翻译：

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setd1a 小鼠的异常皮层合奏和精神分裂症样感觉表型。

背景导致网络“吸引子”不稳定的神经元集合内的同步性破坏可能是神经精神疾病（例如精神分裂症）的一个决定性方面，代表与该疾病相关的多种病因学途径的共同下游汇聚点。使用小鼠遗传模型，我们证明了改变的集合与由 Setd1a 基因功能丧失突变导致的病理感觉皮层处理表型相关，这是一种最近发现的罕见风险基因型，对精神分裂症具有非常高的外显率。方法我们在清醒的头部固定小鼠（Setd1a+/- vs. 野生型同窝对照）在休息和视觉刺激期间使用移动的全场方波光栅（每度 0.04 个周期，每秒 2.0 个周期，100% 对比度，12 个方向）。在时频域中分析多电极记录，以评估刺激引起的振荡和跨层相位同步。结果 Setd1a+/- 小鼠的神经元活动和方向/方向选择性未受影响，但 V1 中细胞对之间的相关性显示，与野生型小鼠相比，在持续和视觉诱发活动中的分布发生了改变。此外，在休息和视觉刺激期间，随着时间的推移，Setd1a+/- 小鼠中的全人群“整体激活”明显不太可靠，导致基本视觉信息的编码不稳定。整体的这种改变与皮质层内和皮质层之间的 alpha 和高伽马波段相位同步的减少相吻合。结论这些结果为精神分裂症的整体假设提供了新的证据，并突出了 Setd1a+/- 小鼠在模拟感觉处理表型方面的效用。