Background

Diminished synaptic gain—the sensitivity of postsynaptic responses to neural inputs—may be a fundamental synaptic pathology in schizophrenia. Evidence for this is indirect, however. Furthermore, it is unclear whether pyramidal cells or interneurons (or both) are affected, or how these deficits relate to symptoms.

Methods

People with schizophrenia diagnoses (PScz) (n = 108), their relatives (n = 57), and control subjects (n = 107) underwent 3 electroencephalography (EEG) paradigms—resting, mismatch negativity, and 40-Hz auditory steady-state response—and resting functional magnetic resonance imaging. Dynamic causal modeling was used to quantify synaptic connectivity in cortical microcircuits.

Results

Classic group differences in EEG features between PScz and control subjects were replicated, including increased theta and other spectral changes (resting EEG), reduced mismatch negativity, and reduced 40-Hz power. Across all 4 paradigms, characteristic PScz data features were all best explained by models with greater self-inhibition (decreased synaptic gain) in pyramidal cells. Furthermore, disinhibition in auditory areas predicted abnormal auditory perception (and positive symptoms) in PScz in 3 paradigms.

Conclusions

First, characteristic EEG changes in PScz in 3 classic paradigms are all attributable to the same underlying parameter change: greater self-inhibition in pyramidal cells. Second, psychotic symptoms in PScz relate to disinhibition in neural circuits. These findings are more commensurate with the hypothesis that in PScz, a primary loss of synaptic gain on pyramidal cells is then compensated by interneuron downregulation (rather than the converse). They further suggest that psychotic symptoms relate to this secondary downregulation.

中文翻译：

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脑电图和功能磁共振成像范式的计算模型表明精神分裂症患者锥体细胞突触增益的持续丧失

 背景

突触增益减少（突触后反应对神经输入的敏感性）可能是精神分裂症的基本突触病理。然而，这方面的证据是间接的。此外，尚不清楚锥体细胞或中间神经元（或两者）是否受到影响，或者这些缺陷与症状有何关系。

 方法

精神分裂症诊断患者 (PScz) ( n = 108)、其亲属 ( n = 57) 和对照受试者 ( n = 107) 接受 3 种脑电图 (EEG) 范式 — 静息、失配负性和 40 Hz 听觉稳态反应和静息功能磁共振成像。动态因果模型用于量化皮质微电路中的突触连接。

 结果

PScz 和对照受试者之间脑电图特征的经典群体差异得到了复制，包括 θ 和其他频谱变化（静息脑电图）增加、失配负性减少以及 40 Hz 功率减少。在所有 4 个范式中，特征性 PScz 数据特征都可以通过锥体细胞中具有更大自我抑制（突触增益减少）的模型得到最好的解释。此外，听觉区域的去抑制在 3 种范式中预测 PScz 的听觉异常（和阳性症状）。

 结论

首先，3种经典范式中PScz的特征性脑电图变化都可归因于相同的潜在参数变化：锥体细胞更大的自我抑制。其次，PScz 的精神病症状与神经回路的去抑制有关。这些发现与以下假设更相符：在 PScz 中，锥体细胞突触增益的主要损失随后通过中间神经元下调（而不是相反）得到补偿。他们进一步表明精神病症状与这种继发性下调有关。